Dietary emulsifier polysorbate 80 exposure accelerates age-related cognitive decline.

Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline.

Metformin synergistically enhances the antitumour activity of Lenvatinib in hepatocellular carcinoma by altering AKT-FOXO3 signalling pathway.

BACKGROUND AND AIMS: Lenvatinib is a first-line drug commonly used in the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is very limited due to drug resistance. Therefore, there is a great need to explore its combination with other agents to achieve better therapeutic effects. Metformin has been demonstrated to show an anti-cancer effect. This study aimed to investigate the combined effect of lenvatinib with metformin in HCC cells both in vitro and in vivo and elucidate the possible molecular mechanisms. METHODS: Flow cytometry, colony formation, CCK-8 and transwell assays were used to study the effect of Lenvatinib-Metformin combination on the malignant behaviour of HCC cells in vitro. Constructing an animal model of tumour-bearing to study the effect of combined drugs on HCC in vivo. Western blot experiments were performed to assess the relationship between AKT and FOXO3 and the cellular translocation of FOXO3. RESULTS: Our results suggested that Lenvatinib and Metformin synergistically inhibited HCC growth and motility. Mechanistically, the combination of Lenvatinib and Metformin synergistically suppressed the activation of the AKT signalling pathway, which in turn reduced the phosphorylation level of downstream effector FOXO3 and induced its nuclear aggregation. In vivo studies further confirmed the synergistic suppression of lenvatinib with metformin in HCC growth. CONCLUSION: The Lenvatinib-Metformin combination may provide a potential therapeutic strategy to improve the prognosis of HCC patients.

MAB-DrNet: Bearing Fault Diagnosis Method Based on an Improved Dilated Convolutional Neural Network.

Rolling bearing fault diagnosis is of great significance to the safe and reliable operation of manufacturing equipment. In the actual complex environment, the collected bearing signals usually contain a large amount of noises from the resonances of the environment and other components, resulting in the nonlinear characteristics of the collected data. Existing deep-learning-based solutions for bearing fault diagnosis perform poorly in classification performance under noises. To address the above problems, this paper proposes an improved dilated-convolutional-neural network-based bearing fault diagnosis method in noisy environments named MAB-DrNet. First, a basic model called the dilated residual network (DrNet) was designed based on the residual block to enlarge the model's perceptual field to better capture the features from bearing fault signals. Then, a max-average block (MAB) module was designed to improve the feature extraction capability of the model. In addition, the global residual block (GRB) module was introduced into MAB-DrNet to further improve the performance of the proposed model, enabling the model to better handle the global information of the input data and improve the classification accuracy of the model in noisy environments. Finally, the proposed method was tested on the CWRU dataset, and the results showed that the proposed method had good noise immunity; the accuracy was 95.57% when adding Gaussian white noises with a signal-to-noise ratio of -6 dB. The proposed method was also compared with existing advanced methods to further prove its high accuracy.

Edge Detection via Fusion Difference Convolution.

Edge detection is a crucial step in many computer vision tasks, and in recent years, models based on deep convolutional neural networks (CNNs) have achieved human-level performance in edge detection. However, we have observed that CNN-based methods rely on pre-trained backbone networks and generate edge images with unwanted background details. We propose four new fusion difference convolution (FDC) structures that integrate traditional gradient operators into modern CNNs. At the same time, we have also added a channel spatial attention module (CSAM) and an up-sampling module (US). These structures allow the model to better recognize the semantic and edge information in the images. Our model is trained from scratch on the BIPED dataset without any pre-trained weights and achieves promising results. Moreover, it generalizes well to other datasets without fine-tuning.

Mesenchymal stromal cell treatment attenuates repetitive mild traumatic brain injury-induced persistent cognitive deficits via suppressing ferroptosis.

The incidence of repetitive mild traumatic brain injury (rmTBI), one of the main risk factors for predicting neurodegenerative disorders, is increasing; however, its underlying mechanism remains unclear. As suggested by several studies, ferroptosis is possibly related to TBI pathophysiology, but its effect on rmTBI is rarely studied. Mesenchymal stromal cells (MSCs), the most studied experimental cells in stem cell therapy, exert many beneficial effects on diseases of the central nervous system, yet evidence regarding the role of MSCs in ferroptosis and post-rmTBI neurodegeneration is unavailable. Our study showed that rmTBI resulted in time-dependent alterations in ferroptosis-related biomarker levels, such as abnormal iron metabolism, glutathione peroxidase (GPx) inactivation, decrease in GPx4 levels, and increase in lipid peroxidation. Furthermore, MSC treatment markedly decreased the aforementioned rmTBI-mediated alterations, neuronal damage, pathological protein deposition, and improved cognitive function compared with vehicle control. Similarly, liproxstatin-1, a ferroptosis inhibitor, showed similar effects. Collectively, based on the above observations, MSCs ameliorate cognitive impairment following rmTBI, partially via suppressing ferroptosis, which could be a therapeutic target for rmTBI.

Treatment response to eribulin and anlotinib in lung metastases from rare perianal adenoid cystic carcinoma: a case report.

Adenoid cystic carcinoma (ACC) is a rare salivary glands tumor and often displays aggressive behavior with frequent relapse and metastasis. The terminal ACC lacks standard treatment guidelines and is always accompanied by poor prognosis. Here, we report a case of rare perianal ACC who received resection and palliative adjuvant radiation. Five years later, PET-computed tomography (CT) showed perianal recurrence and multiple pulmonary metastases. Combined chemotherapy with doxorubicin, carboplatin and cyclophosphamide was applied for two cycles but ineffective. Further next-generation sequencing analysis of perianal tissue demonstrated the v-myb avian myelobastosis viral oncogene homolog and nuclear factor I/B fusion gene and two novel BCL-6 corepressor (BCOR) mutations (p.F1106Tfs*5 and p.L1524Hfs*8). The therapy was switched to eribulin and anlotinib and has been performed for eight cycles. At recent follow-ups, MRI and CT examinations revealed the diminishing perianal and pulmonary lesions. This study presented the first case of perianal ACC with multiple pulmonary metastases and particular BCOR mutations, who presented a durable response to eribulin and anlotinib, providing a potential therapeutic option for advanced refractory ACC.

Complete remission in leptomeningeal metastasis of NSCLC with rare EGFR-SEPT14 fusion treated with osimertinib combined with intrathecal chemotherapy with pemetrexed.

Leptomeningeal metastasis (LM) is one of the most serious complications of non-small cell lung cancer (NSCLC) without standard treatment guidelines and is always accompanied by poor prognosis. Identifying the types of gene mutations is essential to improve the outcome, and an increasing number of rare epidermal growth factor receptor (EGFR) mutations are revealed by next-generation sequencing (NGS). Here, we describe a case of a 56-year-old man who was diagnosed with lung adenocarcinoma and received thoracoscopic resection in May 2015. One year later, LM was confirmed by positive cerebrospinal fluid cytology. Given the existence of EGFR exon 19 deletions, erlotinib was implemented and achieved a short response for 10 months. Then the systemic therapy was changed to osimertinib and obtained clinical remission for 25 months. Owing to the resurgence of violent headache, retching and vomiting, NGS of cerebrospinal fluid was performed and two rare EGFR-SEPT14 fusions were found. Osimertinib combined bevacizumab, chemotherapy (carboplatin and abraxane) and dacomitinib were implemented in turn but ineffective. Thus, osimertinib combined intrathecal chemotherapy with pemetrexed were carried out and gained a complete remission of neurologic symptoms, stable lesions and long-term survival without notable side effects. This study presented the first case of NSCLC-LM harboring particular EGFR-SEPT14 fusions, who showed a durable response to osimertinib and intrathecal pemetrexed, providing a potential therapeutic option for NSCLC-LM patients with this particular mutation.

Heuristic Routing Algorithms for Time-Sensitive Networks in Smart Factories.

Over recent years, traditional manufacturing factories have been accelerating their transformation and upgrade toward smart factories, which are an important concept within Industry 4.0. As a key communication technology in the industrial internet architecture, time-sensitive networks (TSNs) can break through communication barriers between subsystems within smart factories and form a common network for various network flows. Traditional routing algorithms are not applicable for this novel type of network, as they cause unnecessary congestion and latency. Therefore, this study examined the classification of TSN flows in smart factories, converted the routing problem into two graphical problems, and proposed two heuristic optimization algorithms, namely GATTRP and AACO, to find the optimal solution. The experiments showed that the algorithms proposed in this paper could provide a more reasonable routing arrangement for various TSN flows with different time sensitivities. The algorithms could effectively reduce the overall delay by up to 74% and 41%, respectively, with promising operating performances.

A Multi-Objective Task Scheduling Strategy for Intelligent Production Line Based on Cloud-Fog Computing.

With the widespread use of industrial Internet technology in intelligent production lines, the number of task requests generated by smart terminals is growing exponentially. Achieving rapid response to these massive tasks becomes crucial. In this paper we focus on the multi-objective task scheduling problem of intelligent production lines and propose a task scheduling strategy based on task priority. First, we set up a cloud-fog computing architecture for intelligent production lines and built the multi-objective function for task scheduling, which minimizes the service delay and energy consumption of the tasks. In addition, the improved hybrid monarch butterfly optimization and improved ant colony optimization algorithm (HMA) are used to search for the optimal task scheduling scheme. Finally, HMA is evaluated by rigorous simulation experiments, showing that HMA outperformed other algorithms in terms of task completion rate. When the number of nodes exceeds 10, the completion rate of all tasks is greater than 90%, which well meets the real-time requirements of the corresponding tasks in the intelligent production lines. In addition, the algorithm outperforms other algorithms in terms of maximum completion rate and power consumption.

Experimental study on the monotonic mechanical behavior of completely decomposed granite soil reinforced by disposable face-mask chips.

In response to the global outbreak of the coronavirus pandemic (COVID-19), a staggering amount of personal protective equipment, such as disposable face masks, has been used, leading to the urgent environmental issue. This study evaluates the feasibility of mask chips for the soil reinforcement, through triaxial tests on samples mixed with complete decomposed granite (CDG) and mask chips (0%, 0.3%, 0.5%, 1%, 5% by volume). The experimental results show that adding a moderate volumetric amount of mask chips (0.3%-1%) improves the soil strength, especially under high confining pressure. The optimum volumetric content of mask chips obtained by this study is 0.5%, raising the peak shear strength up to 22.3% under the confining stress of 120 kPa. When the volumetric content of mask chips exceeds the optimum value, the peak shear strength decreases accordingly. A limited amount of mask chips also increases the elastic modulus and makes the volumetric response more dilative. By contrast, excessive mask chips create additional voids and shift the strong soil-mask contacts to weak mask-mask contacts. The laser scanning microscope (LSM) and scanning electron microscope (SEM) images on the typical samples demonstrate the microstructure of mask fibers interlocking with soil particles, highly supporting the macro-scale mechanical behavior.

Association of liver abnormalities with in-hospital mortality in patients with COVID-19.

BACKGROUND & AIMS: The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. METHODS: This large retrospective cohort study included 2,073 patients with coronavirus disease 2019 (COVID-19) and definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted, with associated factors and risk of death determined by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19, with and without hepatitis B, were compared after 1:3 propensity score matching. RESULTS: Of the 2,073 patients, 1,282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of aspartate aminotransferase (AST) and direct bilirubin (D-Bil) increased early after symptom onset in deceased patients and showed disparity compared to levels in discharged patients throughout the clinical course of the disease. Abnormal AST (adjusted hazard ratio [HR] 1.39; 95% CI 1.04-1.86, p = 0.027) and D-Bil (adjusted HR 1.66; 95% CI 1.22-2.26; p = 0.001) levels at admission were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes. CONCLUSIONS: Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19-related mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, is necessary in hospitalized patients with COVID-19. LAY SUMMARY: Liver test abnormalities (in particular elevations in the levels of aspartate aminotransferase [AST] and direct bilirubin [D-Bil]) were observed after symptom onset in patients who went on to die of coronavirus disease 2019 (COVID-19). Abnormal levels of AST and D-Bil at admission were independent predictors of COVID-19-related mortality. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes.

Hypoxia-Activated Prodrug Enabling Synchronous Chemotherapy and HIF-1α Downregulation for Tumor Treatment.

The overexpression of HIF-1α in solid tumors due to hypoxia is closely related to drug resistance and consequent treatment failure. Herein, we constructed a hypoxia-activated prodrug named as YC-Dox. This prodrug could be activated under hypoxic conditions and undergo self-immolation to release doxorubicin (Dox) and YC-1 hemisuccinate (YCH-1), which could execute chemotherapy and result in HIF-1α downregulation, respectively. This prodrug is capable of specifically releasing Dox and YCH-1 in response to hypoxia, leading to a substantial synergistic potency and a remarkable cytotoxic selectivity (>8-fold) for hypoxic cancer cells over normoxic healthy cells. The in vivo experiments reveal that this prodrug can selectively aim at hypoxic cancer cells and avoid undesired targeting of normal cells, leading to elevated therapeutic efficacy for tumor treatment and minimized adverse effects on normal tissues.

Loss of PP2A Disrupts the Retention of Radial Glial Progenitors in the Telencephalic Niche to Impair the Generation for Late-Born Neurons During Cortical Development†.

Telencephalic radial glial progenitors (RGPs) are retained in the ventricular zone (VZ), the niche for neural stem cells during cortical development. However, the underlying mechanism is not well understood. To study whether protein phosphatase 2A (PP2A) may regulate the above process, we generate Ppp2cα conditional knockout (cKO) mice, in which PP2A catalytic subunit α (PP2Acα) is inactivated in neural progenitor cells in the dorsal telencephalon. We show that RGPs are ectopically distributed in cortical areas outside of the VZ in Ppp2cα cKO embryos. Whereas deletion of PP2Acα does not affect the proliferation of RGPs, it significantly impairs the generation of late-born neurons. We find complete loss of apical adherens junctions (AJs) in the ventricular membrane in Ppp2cα cKO cortices. We observe abundant colocalization for N-cadherin and PP2Acα in control AJs. Moreover, in vitro analysis reveals direct interactions of N-cadherin to PP2Acα and to ß-catenin. Overall, this study not only uncovers a novel function of PP2Acα in retaining RGPs into the VZ but also demonstrates the impact of PP2A-dependent retention of RGPs on the generation for late-born neurons.

Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI.

Repetitive mild traumatic brain injury (rmTBI) is considered to be an important risk factor for long-term neurodegenerative disorders such as Alzheimer's disease, which is characterized by ß-amyloid abnormalities and impaired cognitive function. Microglial exosomes have been reported to be involved in the transportation, distribution, and clearance of ß-amyloid in Alzheimer's disease. However, their impacts on the development of neurodegeneration after rmTBI are not yet known. The role of miRNAs in microglial exosomes on regulating post-traumatic neurodegeneration was investigated in the present study. We demonstrated that miR-124-3p level in microglial exosomes from injured brain was significantly altered in the acute, sub-acute, and chronic phases after rmTBI. In in vitro experiments, microglial exosomes with upregulated miR-124-3p (EXO-124) alleviated neurodegeneration in repetitive scratch-injured neurons. The effects were exerted by miR-124-3p targeting Rela, an inhibitory transcription factor of ApoE that promotes the ß-amyloid proteolytic breakdown, thereby inhibiting ß-amyloid abnormalities. In mice with rmTBI, the intravenously injected microglial exosomes were taken up by neurons in injured brain. Besides, miR-124-3p in the exosomes was transferred into hippocampal neurons and alleviated neurodegeneration by targeting the Rela/ApoE signaling pathway. Consequently, EXO-124 treatments improved the cognitive outcome after rmTBI, suggesting a promising therapeutic strategy for future clinical translation.

Joint Soft-Hard Attention for Self-Supervised Monocular Depth Estimation.

In recent years, self-supervised monocular depth estimation has gained popularity among researchers because it uses only a single camera at a much lower cost than the direct use of laser sensors to acquire depth. Although monocular self-supervised methods can obtain dense depths, the estimation accuracy needs to be further improved for better applications in scenarios such as autonomous driving and robot perception. In this paper, we innovatively combine soft attention and hard attention with two new ideas to improve self-supervised monocular depth estimation: (1) a soft attention module and (2) a hard attention strategy. We integrate the soft attention module in the model architecture to enhance feature extraction in both spatial and channel dimensions, adding only a small number of parameters. Unlike traditional fusion approaches, we use the hard attention strategy to enhance the fusion of generated multi-scale depth predictions. Further experiments demonstrate that our method can achieve the best self-supervised performance both on the standard KITTI benchmark and the Make3D dataset.

Hydrogen exerts neuroprotection by activation of the miR-21/PI3K/AKT/GSK-3ß pathway in an in vitro model of traumatic brain injury.

Few studies have explored the effect of hydrogen on neuronal apoptosis or impaired nerve regeneration after traumatic brain injury, and the mechanisms involved in these processes are unclear. In this study, we explored neuroprotection of hydrogen-rich medium through activation of the miR-21/PI3K/AKT/GSK-3ß pathway in an in vitro model of traumatic brain injury. Such model adopted PC12 cells with manual scratching. Then, injured cells were cultured in hydrogen-rich medium for 48 hours. Expression of miR-21, p-PI3K, p-Akt, p-GSK-3ß, Bax and Bcl-2 was measured using RT-qPCR, Western blot analysis and immunofluorescence staining. Rate of apoptosis was determined using TUNEL staining. Neuronal regeneration was assessed using immunofluorescence staining. The results showed that hydrogen-rich medium improved neurite regeneration and inhibited apoptosis in the injured cells. Scratch injury was accompanied by up-regulation of miR-21, p-PI3K, p-Akt and p-GSK-3ß. A miR-21 antagomir inhibited the expression of these four molecules, while a PI3K blocker only affected the three proteins and not miR-21. Both the miR-21 antagomir and PI3K blocker reversed the protective effect of hydrogen. In conclusion, hydrogen exerted a neuroprotective effect against neuronal apoptosis and impaired nerve regeneration through activation of miR-21/PI3K/AKT/GSK-3ß signalling in this in vitro model of traumatic brain injury.

Neuron-derived exosomes with high miR-21-5p expression promoted polarization of M1 microglia in culture.

BACKGROUND: Neuroinflammation is a characteristic pathological change of acute neurological deficit and chronic traumatic encephalopathy (CTE) after traumatic brain injury (TBI). Microglia are the key cell involved in neuroinflammation and neuronal injury. The type of microglia polarization determines the direction of neuroinflammation. MiR-21-5p elevated in neurons and microglia after TBI in our previous research. In this study, we explore the influence of miR-21-5p for neuroinflammation by regulating microglia polarization. METHODS: In this study, PC12 and BV2 used to instead of neuron and microglia respectively. The co-cultured transwell system used to simulate interaction of PC12 and BV2 cells in vivo environment. RESULTS: We found that PC12-derived exosomes with containing miR-21-5p were phagocytosed by microglia and induced microglia polarization, meanwhile, the expression of miR-21-5p was increased in M1 microglia cells. Polarization of M1 microglia aggravated the release of neuroinflammation factors, inhibited the neurite outgrowth, increased accumulation of P-tau and promoted the apoptosis of PC12 cells, which formed a model of cyclic cumulative damage. Simultaneously, we also got similar results in vivo experiments. CONCLUSIONS: PC12-derived exosomes with containing miR-21-5p is the essential of this cyclic cumulative damage model. Therefore, regulating the expression of miR-21-5p or the secretion of exosomes may be an important novel strategy for the treatment of neuroinflammation after TBI.

Competing endogenous RNA network and prognostic nomograms for hepatocellular carcinoma patients who underwent R0 resection.

The prognosis of hepatocellular carcinoma (HCC) after R0 resection is unsatisfactory due to the high rate of recurrence. In this study, we investigated the recurrence-related RNAs and the underlying mechanism. The long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression data and clinical information of 247 patients who underwent R0 resection patients with HCC were obtained from The Cancer Genome Atlas. Comparing the 1-year recurrence group (n = 56) with the nonrecurrence group (n = 60), we detected 34 differentially expressed lncRNAs (DElncRNAs), five DEmiRNAs, and 216 DEmRNAs. Of these, three DElncRNAs, hsa-mir-150-5p, and 11 DEmRNAs were selected for constructing the competing endogenous RNA (ceRNA) network. Next, two nomogram models were constructed based separately on the lncRNAs and mRNAs that were further selected by Cox and least absolute shrinkage and selection operator regression analysis. The two nomogram models that showed a high prediction accuracy for disease-free survival with the concordance indexes at 0.725 and 0.639. Further functional enrichment analysis of DEmRNAs showed that the mRNAs in the ceRNA network and nomogram models were associated with immune pathways. Hence, we constructed a hsa-mir-150-5p-centric ceRNA network and two effective nomogram prognostic models, and the related RNAs may be useful as potential biomarkers for predicting recurrence in patients with HCC.

A Large-scale, multicenter serum metabolite biomarker identification study for the early detection of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide. The lack of effective biomarkers for the early detection of HCC results in unsatisfactory curative treatments. Here, metabolite biomarkers were identified and validated for HCC diagnosis. A total of 1,448 subjects, including healthy controls and patients with chronic hepatitis B virus infection, liver cirrhosis, and HCC, were recruited from multiple centers in China. Liquid chromatography-mass spectrometry-based metabolomics methods were used to characterize the subjects' serum metabolic profiles and to screen and validate the HCC biomarkers. A serum metabolite biomarker panel including phenylalanyl-tryptophan and glycocholate was defined. This panel had a higher diagnostic performance than did α-fetoprotein (AFP) in differentiating HCC from a high-risk population of cirrhosis, such as an area under the receiver-operating characteristic curve of 0.930, 0.892, and 0.807 for the panel versus 0.657, 0.725, and 0.650 for AFP in the discovery set, test set, and cohort 1 of the validation set, respectively. In the nested case-control study, this panel had high sensitivity (range 80.0%-70.3%) to detect preclinical HCC, and its combination with AFP provided better risk prediction of preclinical HCC before clinical diagnosis. Besides, this panel showed a larger area under the receiver-operating characteristic curve than did AFP (0.866 versus 0.682) to distinguish small HCC, and 80.6% of the AFP false-negative patients with HCC were correctly diagnosed using this panel in the test set, which was corroborated by the validation set. The specificity and biological relevance of the identified biomarkers were further evaluated using sera from another two cancers and HCC tissue specimens, respectively. Conclusion: The discovered and validated serum metabolite biomarker panel exhibits good diagnostic performance for the early detection of HCC from at-risk populations. (Hepatology 2018;67:662-675).

Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons.

Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neuronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro The microglial exosomes were collected for miRNA microarray analysis, which showed that the expression level of miR-124-3p increased most apparently in the miRNAs. We found that miR-124-3p promoted the anti-inflamed M2 polarization in microglia, and microglial exosomal miR-124-3p inhibited neuronal inflammation in scratch-injured neurons. Further, the mammalian target of rapamycin (mTOR) signaling was implicated as being involved in the regulation of miR-124-3p by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Using the mTOR activator MHY1485 we confirmed that the inhibitory effect of exosomal miR-124-3p on neuronal inflammation was exerted by suppressing the activity of mTOR signaling. PDE4B was predicted to be the target gene of miR-124-3p by pathway analysis. We proved that it was directly targeted by miR-124-3p with a luciferase reporter assay. Using a PDE4B overexpressed lentivirus transfection system, we suggested that miR-124-3p suppressed the activity of mTOR signaling mainly through inhibiting the expression of PDE4B. In addition, exosomal miR-124-3p promoted neurite outgrowth after scratch injury, characterized by an increase on the number of neurite branches and total neurite length, and a decreased expression on RhoA and neurodegenerative proteins [Aß-peptide and p-Tau]. It also improved the neurologic outcome and inhibited neuroinflammation in mice with rTBI. Taken together, increased miR-124-3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via their transfer into neurons. miR-124-3p exerted these effects by targeting PDE4B, thus inhibiting the activity of mTOR signaling. Therefore, miR-124-3p could be a promising therapeutic target for interventions of neuronal inflammation after TBI. miRNAs manipulated microglial exosomes may provide a novel therapy for TBI and other neurologic diseases.-Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons.