Potentially functional genetic variants in interferon regulatory factor family genes are associated with colorectal cancer survival.

Interferon regulatory factor (IRF) family genes play a critical role in colorectal cancer (CRC) development and impact patient survival. This study evaluated the influence of functional single nucleotide polymorphisms (SNPs) in IRF genes on CRC survival, including functional predictions and experimental validations. Multivariate Cox regression analysis identified three linked SNPs as significant survival predictors, with the rs141112353 T/T genotype in the 3'UTR region of IRF6 significantly associated with decreased survival (HR = 1.60, P = 6E-04). Expression quantitative trait loci (eQTL) analysis indicated that the rs141112353 TA > T alteration reduced IRF6 expression. Dual luciferase assays showed lower activity for the T allele in the presence of hsa-miR-548ap-3p. Data from The Cancer Genome Atlas (TCGA) and other databases confirmed lower IRF6 levels in CRC tissues, correlating with worse survival and inversely with M2 macrophage infiltration. In vitro, IRF6 overexpression inhibited CRC cell proliferation and M2 macrophage polarization by downregulating MIF expression. These findings suggest that the IRF6 rs141112353 TA > T variant significantly affects CRC survival, potentially by enhancing miR-548-ap-3p binding affinity.

DEC1 is involved in circadian rhythm disruption-exacerbated pulmonary fibrosis.

BACKGROUND: The alveolar epithelial type II cell (AT2) and its senescence play a pivotal role in alveolar damage and pulmonary fibrosis. Cell circadian rhythm is strongly associated with cell senescence. Differentiated embryonic chondrocyte expressed gene 1 (DEC1) is a very important circadian clock gene. However, the role of DEC1 in AT2 senescence and pulmonary fibrosis was still unclear. RESULTS: In this study, a circadian disruption model of light intervention was used. It was found that circadian disruption exacerbated pulmonary fibrosis in mice. To understand the underlying mechanism, DEC1 levels were investigated. Results showed that DEC1 levels increased in lung tissues of IPF patients and in bleomycin-induced mouse fibrotic lungs. In vitro study revealed that bleomycin and TGF-ß1 increased the expressions of DEC1, collagen-I, and fibronectin in AT2 cells. Inhibition of DEC1 mitigated bleomycin-induced fibrotic changes in vitro and in vivo. After that, cell senescence was observed in bleomycin-treated AT2 cells and mouse models, but these were prevented by DEC1 inhibition. At last, p21 was confirmed having circadian rhythm followed DEC1 in normal conditions. But bleomycin disrupted the circadian rhythm and increased DEC1 which promoted p21 expression, increased p21 mediated AT2 senescence and pulmonary fibrosis. CONCLUSIONS: Taken together, circadian clock protein DEC1 mediated pulmonary fibrosis via p21 and cell senescence in alveolar epithelial type II cells.

A hybrid prediction model of dissolved oxygen concentration based on secondary decomposition and bidirectional gate recurrent unit.

Dissolved oxygen is one of the important comprehensive indicators of river water quality, which reflects the degree of pollution in the water body. Monitoring and predicting dissolved oxygen are an important tool for water quality management, which helps to effectively maintain water ecological balance and prevent environmental problems. A single model cannot describe the dynamic characteristics of dissolved oxygen sequence, which affects the prediction accuracy. In order to obtain more accurate dissolved oxygen prediction results, decomposition techniques are commonly used to extract the main fluctuations and trends of water quality sequences. However, the high-frequency modes obtained from decomposition are still unstable. To solve this problem, this paper proposed a hybrid prediction model of dissolved oxygen concentration based on secondary decomposition and bidirectional gate recurrent unit. Firstly, dissolved oxygen sequence is preliminarily decomposed by complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) and obtain several intrinsic mode functions (IMF). The fuzzy entropy (FE) is calculated to quantify the complexity of the IMF. Then, variational mode decomposition improved by northern goshawk optimization is used to decompose the IMF with higher entropy. The nonlinearity and instability of the sequence are further weakened. Finally, the bidirectional gate recurrent unit (BiGRU) neural network is used to predict each IMF component, and the final prediction result is obtained by reconstructing the prediction results of each component. In order to verify the effectiveness of the proposed model, this paper selects the dissolved oxygen data of Xin'anjiang Reservoir as the research object. The experimental results show that the RMSE, MAE, MAPE, and R2 of the proposed model are 0.1164, 0.0894, 1.0403%, and 0.9939, respectively, which is best among other comparative prediction models (BP, LSTM, GRU, BiGRU, EMD-BiGRU, CEEMDAN-BiGRU, VMD-BiGRU, and GNO-VMD-BiGRU). Therefore, this model effectively deals with high volatility and nonlinear dissolved oxygen data and provides reference for water environment management and ecological protection.

Effects of adding corn steep liquor on bacterial community composition and carbon and nitrogen transformation during spent mushroom substrate composting.

BACKGROUND: Carbon and nitrogen are essential energy and nutrient substances in the composting process. Corn steep liquor (CSL) is rich in soluble carbon and nitrogen nutrients and active substances and is widely used in the biological industry. Nonetheless, limited research has been done on the effect of CSL on composting. This work firstly reveals the effect of adding CSL to bacterial community composition and carbon and nitrogen conversion during composting. This study provides the choice of auxiliary materials for the spent mushroom substrate compost (SMS) and some novel knowledge about the effect of bacterial community on C and N cycling during composting of SMS and CSL. Two treatments were set up in the experiment: 100% spent mushroom substrate (SMS) as CK and SMS + 0.5% CSL (v/v) as CP. RESULTS: The results showed that the addition of CSL enhanced the initial carbon and nitrogen content of the compost, altered the bacterial community structure, and increased the bacterial diversity and relative abundance, which might be beneficial to the conversion and retention of carbon and nitrogen in the composting process. In this paper, network analysis was used to screen the core bacteria involved in carbon and nitrogen conversion. In the CP network, the core bacteria were divided into two categories, synthesizing and degrading bacteria, and there were more synthesizing bacteria than degrading bacteria, so the degradation and synthesis of organic matter were carried out simultaneously, while only degrading bacteria were found in the CK network. Functional prediction by Faprotax identified 53 groups of functional bacteria, among which 20 (76.68% abundance) and 14 (13.15% abundance) groups of functional bacteria were related to carbon and nitrogen conversion, respectively. Adding CSL stimulated the compensatory effect of core and functional bacteria, enhanced the carbon and nitrogen transformation ability, stimulated the activity of low-abundance bacteria, and reduced the competitive relationship between the bacterial groups. This may be why the addition of CSL accelerated the organic matter degradation and increased carbon and nitrogen preservation. CONCLUSIONS: These findings indicate that the addition of CSL promoted the cycling and preservation of carbon and nitrogen in the SMS composts, and the addition of CSL to the compost may be an effective way to dispose of agricultural waste.

Development of an MRI-Based Comprehensive Model Fusing Clinical, Radiomics and Deep Learning Models for Preoperative Histological Stratification in Intracranial Solitary Fibrous Tumor.

BACKGROUND: Accurate preoperative histological stratification (HS) of intracranial solitary fibrous tumors (ISFTs) can help predict patient outcomes and develop personalized treatment plans. However, the role of a comprehensive model based on clinical, radiomics and deep learning (CRDL) features in preoperative HS of ISFT remains unclear. PURPOSE: To investigate the feasibility of a CRDL model based on magnetic resonance imaging (MRI) in preoperative HS in ISFT. STUDY TYPE: Retrospective. POPULATION: Three hundred and ninety-eight patients from Beijing Tiantan Hospital, Capital Medical University (primary training cohort) and 49 patients from Lanzhou University Second Hospital (external validation cohort) with ISFT based on histopathological findings (237 World Health Organization [WHO] tumor grade 1 or 2, and 210 WHO tumor grade 3). FIELD STRENGTH/SEQUENCE: 3.0 T/T1-weighted imaging (T1) by using spin echo sequence, T2-weighted imaging (T2) by using fast spin echo sequence, and T1-weighted contrast-enhanced imaging (T1C) by using two-dimensional fast spin echo sequence. ASSESSMENT: Area under the receiver operating characteristic curve (AUC) was used to assess the performance of the CRDL model and a clinical model (CM) in preoperative HS in the external validation cohort. The decision curve analysis (DCA) was used to evaluate the clinical net benefit provided by the CRDL model. STATISTICAL TESTS: Cohen's kappa, intra-/inter-class correlation coefficients (ICCs), Chi-square test, Fisher's exact test, Student's t-test, AUC, DCA, calibration curves, DeLong test. A P value <0.05 was considered statistically significant. RESULTS: The CRDL model had significantly better discrimination ability than the CM (AUC [95% confidence interval, CI]: 0.895 [0.807-0.912] vs. 0.810 [0.745-0.874], respectively) in the external validation cohort. The CRDL model can provide a clinical net benefit for preoperative HS at a threshold probability >20%. DATA CONCLUSION: The proposed CRDL model holds promise for preoperative HS in ISFT, which is important for predicting patient outcomes and developing personalized treatment plans. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

BMAL1/p53 mediating bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma.

BACKGROUND: Fine particulate matter (PM2.5) is associated with increased incidence and severity of asthma. PM2.5 exposure disrupts airway epithelial cells, which elicits and sustains PM2.5-induced airway inflammation and remodeling. However, the mechanisms underlying development and exacerbation of PM2.5-induced asthma were still poorly understood. The aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a major circadian clock transcriptional activator that is also extensively expressed in peripheral tissues and plays a crucial role in organ and tissue metabolism. RESULTS: In this study, we found PM2.5 aggravated airway remodeling in mouse chronic asthma, and exacerbated asthma manifestation in mouse acute asthma. Next, low BMAL1 expression was found to be crucial for airway remodeling in PM2.5-challenged asthmatic mice. Subsequently, we confirmed that BMAL1 could bind and promote ubiquitination of p53, which can regulate p53 degradation and block its increase under normal conditions. However, PM2.5-induced BMAL1 inhibition resulted in up-regulation of p53 protein in bronchial epithelial cells, then increased-p53 promoted autophagy. Autophagy in bronchial epithelial cells mediated collagen-I synthesis as well as airway remodeling in asthma. CONCLUSIONS: Taken together, our results suggest that BMAL1/p53-mediated bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma. This study highlights the functional importance of BMAL1-dependent p53 regulation during asthma, and provides a novel mechanistic insight into the therapeutic mechanisms of BMAL1. Video Abstract.

Neuroprotective Effect of Dexmedetomidine on Cerebral Ischemia-Reperfusion Injury in Rats.

Background: The number of patients having ischemic stroke is increasing year on year. The anesthetic adjuvant dexmedetomidine is neuroprotective in rats and has potential for use in the treatment of ischemic stroke. Objective: The neuroprotective mechanism of dexmedetomidine in cerebral ischemia-reperfusion injury was studied in relation to its regulation of the oxidative stress response, astrocyte response, microglia overactivation, and apoptosis-related protein expression. Methods: We randomly and equally divided 25 male Sprague-Dawley rats into 5 groups: a sham-operation group, an ischemia-reperfusion injury group, and low-, medium-, and high-dose dexmedetomidine groups. A rat model of focal cerebral ischemia-reperfusion injury was established by embolization of the right middle cerebral artery for 60 minutes and reperfusion for 2 hours. The volume of cerebral infarction was calculated by triphenyl tetrazolium chloride staining. The protein expression levels of caspase-3, methionyl aminopeptidase 2 (MetAP2 or MAP2), glial fibrillary acidic protein, and allograft inflammatory factor 1 (AIF-1) in the cerebral cortex were determined by Western blot and immunohistochemistry. Results: The volume of cerebral infarction in rats decreased with increasing dose of dexmedetomidine (P = .039, 95% CI = .027 to .044). The expression levels of caspase-3, glial fibrillary acidic protein, and allograft inflammatory factor 1 and the amount of 4-hydroxynonenal decreased with increasing doses of dexmedetomidine (P = .033, 95% CI = .021 to .037). Methionyl aminopeptidase 2 (MetAP2 or MAP2) expression increased with increasing doses of dexmedetomidine (P = .023, 95% CI = .011 to .028). Conclusion: Dexmedetomidine has a dose-dependent protective effect on cerebral ischemic injury in rats. The neuroprotective effects of dexmedetomidine are achieved, in part, by reducing the oxidative stress response, inhibiting glial overactivation, and inhibiting expression levels of apoptosis-related proteins.

Human apolipoprotein E isoforms are differentially sialylated and the sialic acid moiety in ApoE2 attenuates ApoE2-Aß interaction and Aß fibrillation.

The APOE genotype is the most prominent genetic risk factor for the development of late-onset Alzheimer''s disease (LOAD); however, the underlying mechanisms remain unclear. In the present study, we found that the sialylation profiles of ApoE protein in the human brain are significantly different among the three isoforms, with ApoE2 exhibiting the most abundant sialic acid modification whereas ApoE4 had the least. We further observed that the sialic acid moiety in ApoE2 significantly affected the interaction between ApoE2 and Aß peptides. The removal of sialic acid in ApoE2 increased the ApoE2 binding affinity for the Aß17-24 region of Aß and promoted Aß fibrillation. These findings provide a plausible explanation for the well-documented differential roles of ApoE isoforms in Aß pathogenesis. Specifically, compared to the other two isotypes, the higher expression of sialic acid in ApoE2 may contribute to the less potent interaction between ApoE2 and Aß and ultimately the slower rate of brain Aß deposition, a mechanism thought to underlie ApoE2-mediated decreased risk for AD. Future studies are warranted to determine whether the differential sialylation in ApoE isoforms may also contribute to some of their other distinct properties, such as their divergent preferences in associations with lipids and lipoproteins, as well as their potential impact on neuroinflammation through modulation of microglial Siglec activity. Overall, our findings lead to the insight that the sialic acid structure is an important posttranslational modification (PTM) that alters ApoE protein functions with relevance for AD.

Identifying and distinguishing of essential tremor and Parkinson's disease with grouped stability analysis based on searchlight-based MVPA.

BACKGROUND: Since both essential tremor (ET) and Parkinson's disease (PD) are movement disorders and share similar clinical symptoms, it is very difficult to recognize the differences in the presentation, course, and treatment of ET and PD, which leads to misdiagnosed commonly. PURPOSE: Although neuroimaging biomarker of ET and PD has been investigated based on statistical analysis, it is unable to assist the clinical diagnosis of ET and PD and ensure the efficiency of these biomarkers. The aim of the study was to identify the neuroimaging biomarkers of ET and PD based on structural magnetic resonance imaging (MRI). Moreover, the study also distinguished ET from PD via these biomarkers to validate their classification performance. METHODS: This study has developed and implemented a three-level machine learning framework to identify and distinguish ET and PD. First of all, at the model-level assessment, the searchlight-based machine learning method has been used to identify the group differences of patients (ET/PD) with normal controls (NCs). And then, at the feature-level assessment, the stability of group differences has been tested based on structural brain atlas separately using the permutation test to identify the robust neuroimaging biomarkers. Furthermore, the identified biomarkers of ET and PD have been applied to classify ET from PD based on machine learning techniques. Finally, the identified biomarkers have been compared with the previous findings of the biology-level assessment. RESULTS: According to the biomarkers identified by machine learning, this study has found widespread alterations of gray matter (GM) for ET and large overlap between ET and PD and achieved superior classification performance (PCA + SVM, accuracy = 100%). CONCLUSIONS: This study has demonstrated the significance of a machine learning framework to identify and distinguish ET and PD. Future studies using a large data set are needed to confirm the potential clinical application of machine learning techniques to discern between PD and ET.

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer.

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two-stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10-6 , false discovery rate < 0.01). This locus containing seven single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55-2.54, P = 6.8 × 10-8 ). Further analysis of ChIP-sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis-regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene-set enrichment analysis. In vitro, RNAi-mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

Rapid screening and isolation of antioxidants from Eupatorium lindleyanum DC. using CCC target-guided by on-line HPLC-DPPH assay.

Counter-current chromatography (CCC) target-guided by on-line HPLC with post-column DPPH assay was established for efficient screening and isolation of large amount of antioxidants from Eupatorium lindleyanum DC. On-line HPLC with post-column DPPH reaction was used to screen the antioxidants and optimize the biphasic solvent system of CCC, then the targeted peaks were purified using CCC. In the present study, three compounds, nepetin, cirsiliol and jaceosidin, were targeted and successively separated from n-butanol fraction of E. lindleyanum DC. by this strategy. All three compounds showed strong DPPH radical scavenging activity. These results confirmed that the strategy would be an efficient and effective method to isolate antioxidants from complex mixtures.

Functional variation of SLC52A3 rs13042395 predicts survival of Chinese gastric cancer patients.

The solute carrier family 52 member 3 (SLC52A3) gene encodes riboflavin transporter protein which is essential to maintain mitochondrial function in cells. In our research, we found that SLC52A3 rs13042395 C > T variation was significantly associated with poor survival in a 926 Chinese gastric cancer (GCa) patients cohort (CC/CT genotype versus TT genotype, HR = 0.57, 95%CI (0.40-0.82), log-rank P = 0.015). The SLC52A3 rs13042395 C > T change led to its increased mRNA expression according to expression quantitative trait loci analysis (P = 0.0029). In vitro, it was revealed that rs13042395 C allele had higher binding affinity to inhibitory transcription factor Meis homeobox 1 (MEIS1) compared with T allele, knock-down of MEIS1 could up-regulate SLC52A3, and overexpression of SLC52A3 contributed to the increased ability of proliferation, colony formation, migration and invasion in GCa cells. Subsequently, the bioinformatics analysis combined with experiments in vitro suggested that Gap junction protein alpha 1 (GJA1) was the downstream effector of SLC52A3, SLC52A3 may promote the GCa cells aggressiveness by down-regulating the GJA1 expression. Overall, SLC52A3 genetic variant rs13042395 C > T change was associated with poorer survival in Chinese GCa patients and increased SLC52A3 expression by interaction with MEIS1. SLC52A3 promoted the GCa cells aggressiveness by down-regulating the GJA1 expression.

Noninvasive Brain Delivery and Efficacy of BDNF to Stimulate Neuroregeneration and Suppression of Disease Relapse in EAE Mice.

The number of FDA-approved protein drugs (biologics), such as antibodies, antibody-drug conjugates, hormones, and enzymes, continues to grow at a rapid rate; most of these drugs are used to treat diseases of the peripheral body. Unfortunately, most of these biologics cannot be used to treat brain diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), and brain tumors in a noninvasive manner due to their inability to permeate the blood-brain barrier (BBB). Therefore, there is a need to develop an effective method to deliver protein drugs into the brain. Here, we report a proof of concept to deliver a recombinant brain-derived neurotrophic factor (BDNF) to the brains of healthy and experimental autoimmune encephalomyelitis (EAE) mice via intravenous (iv) injections by co-administering BDNF with a BBB modulator (BBBM) peptide ADTC5. Western blot evaluations indicated that ADTC5 enhanced the brain delivery of BDNF in healthy SJL/elite mice compared to BDNF alone and triggered the phosphorylation of TrkB receptors in the brain. The EAE mice treated with BDNF + ADTC5 suppressed EAE relapse compared to those treated with BDNF alone, ADTC5 alone, or vehicle. We further demonstrated that brain delivery of BDNF induced neuroregeneration via visible activation of oligodendrocytes, remyelination, and ARC and EGR1 mRNA transcript upregulation. In summary, we have demonstrated that ADTC5 peptide modulates the BBB to permit noninvasive delivery of BDNF to exert its neuroregeneration activity in the brains of EAE mice.

Comprehensive bioinformatics analysis of mRNA expression profiles and identification of a miRNA-mRNA network associated with lupus nephritis.

OBJECTIVE: Lupus nephritis (LN) is one of the serious complications of systemic lupus erythematosus. The aim of this study was to identify core genes and pathways involved in the pathogenesis of LN. METHODS: We screened differentially expressed genes (DEGs) in LN patients using mRNA expression profile data from the Gene Expression Omnibus. The functional and pathway enrichment analysis of DEGs was performed utilizing the Database for annotation, Visualization and Integrated Discovery. Target genes with differentially expressed miRNAs (DEMIs) were predicted using the miRTarBase database, and the intersection between these target genes and DEGs was selected to be studied further. RESULTS: In total, 107 common DEGs (CDEGs) were identified from the Tub_LN group and Glom_LN group, and 66 DEMIs were identified. Fifty-three hub genes and two significant modules were identified from the protein-protein interaction (PPI) network, and a miRNA-mRNA network was constructed. The CDEGs, module genes in the PPI network and genes intersecting with the CDEGs and target genes of DEMIs were all associated with the PI3K-Akt signalling pathway. CONCLUSION: In summary, this study reveals some crucial genes and pathways potentially involving in the pathogenesis of LN. These findings provide a new insight for the research and treatment of LN.

Noninvasive evaluation of esophageal varices in cirrhotic patients based on spleen hemodynamics: a dual-energy CT study.

OBJECTIVE: To evaluate noninvasively the severity of esophageal varices (EV) in cirrhotic patients using splenic hemodynamics obtained with dual-energy CT. METHODS: We retrospectively analyzed 72 cirrhotic patients with EV between December 2018 and June 2019. Patients were divided into three groups: mild (EV1), medium (EV2), or severe (EV3) EV groups based on severity of EV assessed by endoscopy. An additional control group included 20 patients with normal liver CT. All patients underwent contrast-enhanced dual-energy CT. The iodine weight in spleen (IW-S) was calculated as IW-S = IC-S (iodine concentration in spleen) × V-S (spleen volume). Differences between EV and control groups were analyzed using one-way analysis of variance with Welch's correction. Games-Howell test made further pairwise comparison. The diagnostic value of IW-S on high-risk EV (EV2, EV3, or EV1 with red color sign) was evaluated using the ROC curve. p < 0.05 indicated statistical significance. RESULTS: The overall difference of IW-S between the control and EV groups was statistically significant (p < 0.001). Patients with more severe EV had higher IW-S values. Pairwise comparisons showed that except for control vs. EV1 groups, the IW-S between any other two groups was significantly different (p < 0.05). With a cutoff value at 1087 mg, the AUC for using IW-S for the detection of high-risk EV was 0.87 (95% CI 0.77~0.94). Sensitivity and specificity were 84.9% and 84.2%, respectively. CONCLUSION: IW-S obtained with dual-energy CT can noninvasively predict EV severity. KEY POINTS: • A higher iodine weight in spleen (IW-S) was observed in case of severe esophageal varices. • Cirrhotic patients have significantly higher IW-S than normal-liver patients. • IW-S in dual-energy CT maybe used to evaluate the severity of EV.

Assessing Liver Hemodynamics in Children With Cholestatic Cirrhosis by Use of Dual-Energy Spectral CT.

OBJECTIVE. The purpose of this study was to evaluate the value of dual-energy CT (DECT) in assessing liver hemodynamics in children with cholestatic cirrhosis. MATERIALS AND METHODS. The cases of 60 children with cholestatic cirrhosis (study group) and 15 children with inherited metabolic diseases but normal liver function (control group) were retrospectively evaluated. Enhanced CT scans were obtained in spectral imaging mode. Iodine concentration (IC) of hepatic parenchyma in the arterial phase (ICA) and portal venous phase (ICP) was measured on iodine-water material decomposition images. The hepatic arterial iodine fraction (AIF) was calculated as: AIF = ICA / ICP. The ICA, ICP, and AIF of children in the control and study groups were analyzed by one-way ANOVA and post hoc test with Bonferroni correction. The radiation dose was recorded. RESULTS. There were differences in ICA and AIF between the control and study groups. The values in patients in the Child-Pugh class C group were the highest and those in the control group the lowest (p < 0.05). Statistically significant differences in ICP were not found (p > 0.05). Specifically, the multiple comparison results indicated that there were differences in both ICA and AIF in most of the groups (p < 0.05). The volume CT dose index value for all patients was the same at 10.14 mGy for each enhanced phase, and the total dose-length product varied between 402.68 and 679.18 mGy-cm. CONCLUSION. ICA and AIF obtained at dual-energy CT can be used as semiquantitative indicators to evaluate the liver hemodynamics of children with cholestatic cirrhosis.

Research progress of computer aided diagnosis system for pulmonary nodules in CT images.

BACKGROUND AND OBJECTIVE: Since CAD (Computer Aided Diagnosis) system can make it easier and more efficient to interpret CT (Computer Tomography) images, it has gained much attention and developed rapidly in recent years. This article reviews recent CAD techniques for pulmonary nodule detection and diagnosis in CT Images. METHODS: CAD systems can be classified into computer-aided detection (CADe) and computer-aided diagnosis (CADx) systems. This review reports recent researches of both systems, including the database, technique, innovation and experimental results of each work. Multi-task CAD systems, which can handle segmentation, false positive reduction, malignancy prediction and other tasks at the same time. The commercial CAD systems are also briefly introduced. RESULTS: We have found that deep learning based CAD is the mainstream of current research. The reported sensitivity of deep learning based CADe systems ranged between 80.06% and 94.1% with an average 4.3 false-positive (FP) per scan when using LIDC-IDRI dataset, and between 94.4% and 97.9% with an average 4 FP/scan when using LUNA16 dataset, respectively. The overall accuracy of deep learning based CADx systems ranged between 86.84% and 92.3% with an average AUC of 0.956 reported when using LIDC-IDRI dataset. CONCLUSIONS: We summarized the current tendency and limitations as well as future challenges in this field. The development of CAD needs to meet the rigid clinical requirements, such as high accuracy, strong robustness, high efficiency, fine-grained analysis and classification, and to provide practical clinical functions. This review provides helpful information for both engineering researchers and radiologists to learn the latest development of CAD systems.

Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention.

Humans possess three genetic isoforms of apolipoprotein E (ApoE)-ApoE2, ApoE3, and ApoE4-that confer differential risk for Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. This study sought to investigate the impact of human ApoE isoforms on brain energy metabolism, an area significantly perturbed in preclinical AD. A TaqMan custom array was performed to examine the expression of a total of 43 genes involved in glucose and ketone body transport and metabolism, focusing on pathways leading to the generation of acetyl-CoA, in human ApoE gene-targeted replacement female mice. Consistent with our previous findings, brains expressing ApoE2 exhibited the most robust profile, whereas brains expressing ApoE4 displayed the most deficient profile on the uptake and metabolism of glucose, the primary fuel for the brain. Specifically, the three ApoE brains differed significantly in facilitated glucose transporters, which mediate the entry of glucose into neurons, and hexokinases, which act as the "gateway enzyme" in glucose metabolism. Interestingly, on the uptake and metabolism of ketone bodies, the secondary energy source for the brain, ApoE2 and ApoE4 brains showed a similar level of robustness, whereas ApoE3 brains presented a relatively deficient profile. Further, ingenuity pathway analysis indicated that the PPAR-γ/PGC-1α signaling pathway could be activated in the ApoE2 brain and inhibited in the ApoE4 brain. Notably, PGC-1α overexpression ameliorated ApoE4-induced deficits in glycolysis and mitochondrial respiration. Overall, our data provide additional evidence that human ApoE isoforms differentially modulate brain bioenergetic metabolism, which could serve as a potential mechanism contributing to their discrete risk impact in AD.SIGNIFICANCE STATEMENT We uncovered hexokinase as a key cytosolic point in the glucose metabolism that is differentially modulated by the three ApoE genotypes. The differences in hexokinase expression and activity exhibited in the three ApoE brains may underlie their distinct impact on brain glucose utilization and further susceptibility to AD. Therefore, a therapeutic approach that could circumvent the deficiencies in the cytosolic metabolism of glucose by providing glucose metabolizing intermediates, e.g., pyruvate, may hold benefits for ApoE4 carriers, who are at high risk for AD. The bioenergetic robustness may translate into enhanced synaptic activity and, ultimately, reduces the risk of developing AD and/or delays the onset of clinical manifestation.

Effects of Ginsenoside Rb1 on Expressions of Phosphorylation Akt/Phosphorylation mTOR/Phosphorylation PTEN in Artificial Abnormal Hippocampal Microenvironment in Rats.

Artificial abnormal microenvironment caused by microperfusion of L-glutamate (Glu) and Ca2+ in the hippocampus results in neuron damage, which is closely related to cerebral ischemia. Ginsenoside Rb1, a compound from Panax notoginseng, was previously used to counter the artificial abnormal hippocampal environment in a microperfusion model. In addition, while the Akt/mTOR/PTEN signaling pathway has been shown to mediate neuronprotection in cerebral ischemia, whether this pathway is involved in the neuroprotection of ginsenoside Rb1 is unknown. Here SH-SY5Y cells exposed to OGD/R injury in treated with LY294002, ginsenoside Rb1, ginsenoside Rb1+ LY294002. Expressions of phosphorylation (P-)Akt/P-mTOR/P-PTEN (24 h after OGD/R) were detected by Western blotting. Effects were examined via the memory function of rats (by Morris water maze test), morphological changes in pyramidal cell (by histology), and mRNA expression (by qRT-PCR) and phosphorylation (P-) (by Western blotting and immunohistochemical staining) of Akt, P-mTOR, and P-PTEN in the hippocampus. The memory deficit of rats and pyramidal cellular necrosis and apoptosis in the CA1 region of hippocampus after microperfusion of Glu and Ca2+ were dose dependently alleviated by ginsenoside Rb1.Moreover,Western blot showed that ginsenoside Rb1 increased the expressions of P-Akt, P-mTOR and reduced P-PTEN in vivo and vitro. Thus, the potent neuroprotection of ginsenoside Rb1 in artificial abnormal microenvironment is, at least partially, related to the activation of P-AKT/P-mTOR signaling pathway and inhibition of P-PTEN protein.

ß-Arrestin-biased AT1R stimulation promotes extracellular matrix synthesis in renal fibrosis.

The renin-angiotensin system plays a critical role in the progression of renal fibrosis. Angiotensin II type 1 receptor (AT1R) belongs to the B family of the G protein-coupled receptor (GPCR) family. ß-Arrestins are known as negative regulators of GPCRs. Recently, ß-arrestins have been found to regulate multiple intracellular signaling pathways independent of G proteins. In this study we investigated the role of ß-arrestins in regulating extracellular matrix (ECM) synthesis in renal fibrosis. The rat kidney fibroblast cell line (NRK-49F) was treated with the ß-arrestin biased agonist [1-sar, 4, 8-ile]angiotensin II (SII), which does not initiate AT1R-G protein signaling. The cells were transfected with recombinant adenoviruses expressing ß-arrestin-2 gene or small-interfering RNA (siRNA) targeting ß-arrestin-2. The unilateral ureteral obstruction (UUO) model was used in vivo. mRNA and protein levels of ß-arrestin-2, not ß-arrestin-1, were significantly upregulated in the UUO kidney tissues. SII induced the tight binding of ß-arrestin-2 with AT1R. SII increased the synthesis of collagen I and fibronectin in NRK-49F, which were abolished when pretreated with candesartan (AT1R blocker). Transfection of siRNA targeting ß-arrestin-2 decreased the effects of SII on ECM synthesis. Overexpression of ß-arrestin-2 enhanced SII-stimulated ECM synthesis. SII induced ERK1/2 phosphorylation in NRK-49F. Transfection of siRNA targeting ß-arrestin-2 inhibited ERK phosphorylation. Overexpression of ß-arrestin-2 increased ERK1/2 phosphorylation. Our study first showed that AT1R-ß-arrestin-2 pathway signaling plays an important role in renal fibrosis, although it was previously believed that the AT1R-G protein pathway plays a major role. Targeting ß-arrestin-2 may be a potential therapeutic agent for renal fibrosis.