A pattern-discovery-based outcome predictive tool integrated with clinical data repository: design and a case study on contrast related acute kidney injury.

BACKGROUND: Clinical data repositories (CDR) including electronic health record (EHR) data have great potential for outcome prediction and risk modeling. We built a prediction tool integrated with CDR based on pattern discovery and demonstrated a case study on contrast related acute kidney injury (AKI). METHODS: Patients undergoing cardiac catheterization from January 2015 to April 2017 were included. AKI was identified based on Acute Kidney Injury Network definition. Predictive model including 16 variables covered in existing AKI models was built. A visual analytics tool based on pattern discovery was trained on 70% data up to August 2016 with three interactive knowledge incorporation modes to develop 3 models: (1) pure data-driven, (2) domain knowledge, and (3) clinician-interactive, which were tested and compared on 30% consecutive cases dated afterwards. RESULTS: Among 2560 patients in the final dataset, 189 (7.3%) had AKI. We measured 4 existing models, whose areas under curves (AUCs) of receiver operating characteristics curve for the test dataset were 0.70 (Mehran's), 0.72 (Chen's), 0.67 (Gao's) and 0.62 (AGEF), respectively. A pure data-driven machine learning method achieves AUC of 0.72 (Easy Ensemble). The AUCs of our 3 models are 0.77, 0.80, 0.82, respectively, with the last being top where physician knowledge is incorporated. CONCLUSIONS: We developed a novel pattern-discovery-based outcome prediction tool integrated with CDR and purely using EHR data. On the case of predicting contrast related AKI, the tool showed user-friendliness by physicians, and demonstrated a competitive performance in comparison with the state-of-the-art models.

Nitration of Drp1 provokes mitophagy activation mediating neuronal injury in experimental autoimmune encephalomyelitis.

Active autophagy/mitophagy could mediate neurodegeneration and motor disabilities in multiple sclerosis (MS). Mitochondrial recruitment of dynamin-related protein 1 (Drp1) is a crucial step to initiate mitophagy. Peroxynitrite (ONOO-) could be a player in MS pathology but the mechanisms remain unknown. We used animal model of experimental autoimmune encephalomyelitis (EAE) and tested whether ONOO- mediates Drp1 assembly in mitochondria for mitophagy and aggravates MS pathology. We found that autophagy/mitophagy activation was coincidently increased with axonal damage, apoptosis and disease progression in active EAE mice, which were remarkably attenuated by mitochondrial division/mitophagy inhibitor Mdivi-1. Importantly, increased ONOO- production was companied with Drp1 mitochondrial recruitment, PINK1/Parkin-mediated mitophagy, axonal degeneration and neuronal cell death, which were reversed by peroxynitrite decomposition catalyst (PDC). Furthermore, ONOO- production induced Drp1 nitration, promoted Drp1 assembly and mitochondrial recruitment for mitophagy activation, contributing to the EAE pathology. Together, we conclude that ONOO- serves as a key mediator in Drp1 nitration modification and assembly for facilitating mitophagy activation. Targeting ONOO--mediated Drp1 assembly and mitochondrial recruitment could be an important therapeutic strategy for multiple sclerosis treatment.

Naringin Attenuates Cerebral Ischemia-Reperfusion Injury Through Inhibiting Peroxynitrite-Mediated Mitophagy Activation.

Excessive autophagy/mitophagy plays important roles during cerebral ischemia-reperfusion (I/R) injury. Peroxynitrite (ONOO-), a representative reactive nitrogen species, mediates excessive mitophagy activation and exacerbates cerebral I/R injury. In the present study, we tested the hypothesis that naringin, a natural antioxidant, could inhibit ONOO--mediated mitophagy activation and attenuate cerebral I/R injury. Firstly, we demonstrated that naringin possessed strong ONOO- scavenging capability and also inhibited the production of superoxide and nitric oxide in SH-SY5Y cells exposed to 10 h oxygen-glucose-deprivation plus 14 h of reoxygenation or ONOO- donor 3-morpholinosydnonimine conditions. Naringin also inhibited the expression of NADPH oxidase subunits and iNOS in rat brains subjected to 2 h ischemia plus 22 h reperfusion. Next, we found that naringin was able to cross the blood-brain barrier, and naringin decreased neurological deficit score, reduced infarct size, and attenuated apoptotic cell death in the ischemia-reperfused rat brains. Furthermore, naringin reduced 3-nitrotyrosine formation, decreased the ratio of LC3-II to LC3-I in mitochondrial fraction, and inhibited the translocation of Parkin to the mitochondria. Taken together, naringin could be a potential therapeutic agent to prevent the brain from I/R injury via attenuating ONOO--mediated excessive mitophagy.

Peroxynitrite enhances self-renewal, proliferation and neuronal differentiation of neural stem/progenitor cells through activating HIF-1α and Wnt/ß-catenin signaling pathway.

Hypoxic/ischemic stimulation could mediate growth and differentiation of neural stem/progenitor cells (NSCs) into mature neurons but its underlying mechanisms are largely unclear. Peroxynitrite formation is considered as a crucial pathological process contributing to cerebral ischemia-reperfusion injury. In the present study, we tested the hypothesis that peroxynitrite at low concentration could function as redox signaling to promote the growth of NSCs under hypoxic/ischemic conditions. Increased NSCs proliferation was accompanied by peroxynitrite production in the rat brains with 1 h of ischemia plus 7 days of reperfusion in vivo. Cell sorting experiments revealed that endogenous peroxynitrite level affected the capacity of proliferation and self-renewal in NSCs in vitro. Hypoxia stimulated peroxynitrite production and promoted NSCs self-renewal, proliferation and neuronal differentiation whereas treatments of peroxynitrite decomposition catalysts (PDCs, FeTMPyP and FeTPPS) blocked the changes in NSCs self-renewal, proliferation and neuronal differentiation. Exogenous peroxynitrite treatment revealed similar effects to promote NSCs proliferation, self-renewal and neuronal differentiation. Furthermore, the neurogenesis-promoting effects of peroxynitrite were partly through activating HIF-1α correlated with enhanced Wnt/ß-catenin signaling pathway. In conclusion, peroxynitrite could be a cellular redox signaling for promoting NSCs proliferation, self-renewal and neuronal differentiation and peroxynitrite production could contribute to neurogenesis in ischemic/hypoxic NSCs.

Inhibition of Peroxynitrite-Induced Mitophagy Activation Attenuates Cerebral Ischemia-Reperfusion Injury.

Activated autophagy/mitophagy has been intensively observed in ischemic brain, but its roles remain controversial. Peroxynitrite (ONOO-), as a representative of reactive nitrogen species, is considered as a critical neurotoxic factor in mediating cerebral ischemia-reperfusion (I/R) injury, but its roles in autophagy/mitophagy activation remain unclear. Herein, we hypothesized that ONOO- could induce PINK1/Parkin-mediated mitophagy activation via triggering dynamin-related protein 1 (Drp1) recruitment to damaged mitochondria, contributing to cerebral I/R injury. Firstly, we found PINK1/Parkin-mediated mitophagy activation was predominant among general autophagy, leading to rat brain injury at the reperfusion phase after cerebral ischemia. Subsequently, increased nitrotyrosine was found in the plasma of ischemic stroke patients and ischemia-reperfused rat brains, indicating the generation of ONOO- in ischemic stroke. Moreover, in vivo animal experiments illustrated that ONOO- was dramatically increased, accompanied with mitochondrial recruitment of Drp1, PINK1/Parkin-mediated mitophagy activation, and progressive infarct size in rat ischemic brains at the reperfusion phase. FeTMPyP, a peroxynitrite decomposition catalyst, remarkably reversed mitochondrial recruitment of Drp1, mitophagy activation, and brain injury. Intriguingly, further study revealed that ONOO- induced tyrosine nitration of Drp1 peptide, which might contribute to mitochondrial recruitment of Drp1 for mitophagy activation. In vitro cell experiments yielded consistent results with in vivo animal experiments. Taken together, all above findings support the hypothesis that ONOO--induced mitophagy activation aggravates cerebral I/R injury via recruiting Drp1 to damaged mitochondria.

Association Patterns of Ontological Features Signify Electronic Health Records in Liver Cancer.

Electronic Health Record (EHR) system enables clinical decision support. In this study, a set of 112 abdominal computed tomography imaging examination reports, consisting of 59 cases of hepatocellular carcinoma (HCC) or liver metastases (so-called HCC group for simplicity) and 53 cases with no abnormality detected (NAD group), were collected from four hospitals in Hong Kong. We extracted terms related to liver cancer from the reports and mapped them to ontological features using Systematized Nomenclature of Medicine (SNOMED) Clinical Terms (CT). The primary predictor panel was formed by these ontological features. Association levels between every two features in the HCC and NAD groups were quantified using Pearson's correlation coefficient. The HCC group reveals a distinct association pattern that signifies liver cancer and provides clinical decision support for suspected cases, motivating the inclusion of new features to form the augmented predictor panel. Logistic regression analysis with stepwise forward procedure was applied to the primary and augmented predictor sets, respectively. The obtained model with the new features attained 84.7% sensitivity and 88.4% overall accuracy in distinguishing HCC from NAD cases, which were significantly improved when compared with that without the new features.

Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke.

INTRODUCTION: Roles of autophagy/mitophagy activation in ischemic stroke remain controversial. To elucidate potential reasons, we analyze the factors responsible for divergent results in literatures. Reactive nitrogen species (RNS) are important cytotoxic factors in ischemic stroke. Herein, we particularly discuss the roles played by RNS in autophagy/mitophagy and ischemic brain injury. Areas covered: Following factors should be considered in the studies on autophagy/mitophagy in ischemic stroke: (1) Protocols for administration of autophagy regulators including administration time points, routes and doses, etc.; (2) Specificity of autophagy regulators; (3) Animal models of cerebral ischemia with or without reperfusion. In the underlying mechanisms of autophagy/mitophagy, we particularly discuss the potential roles of RNS in mediating excessive autophagy/mitophagy during cerebral ischemia/reperfusion injury. Expert opinion: Emphasis should be given to the following aspects in future studies: (1) Targeting RNS and related cellular signaling pathways in the regulation of autophagy/mitophagy might be a promising strategy for developing novel drugs as well as combined therapy for thrombolytic treatment to reach better outcomes for ischemic stroke; (2) Developing circulating plasma biomarkers linking RNS-mediated autophagy/mitophagy to the magnitude of ischemic brain injury will benefit for stroke treatment. Subsequently, RNS could be dominant therapeutic targets to regulate autophagy/mitophagy for ischemic stroke.

Neuroprotective effects of Tongmai Yizhi Decoction () against Alzheimer's disease through attenuating cyclin-dependent kinase-5 expression.

OBJECTIVES: To explore the protective effects of Tongmai Yizhi Decoction (, TYD), a Chinese herb complex prescription against the impairment of cognitive functions and memory loss in amyloid beta 1-40 (Aß1-40) peptide and ibotenic (IBO)-induced Alzheimer's disease (AD) model rats. METHODS: The in vivo model was established by injecting Aß1-40 and IBO into left hippocampal CA1 area of Sprague-Dawley (SD) rat to mimic AD. Totally 32 SD rats were divided into 4 groups, including sham operation group, AD model group, TYD group [AD rats treated with TYD at the dosage of 19.44 g/(kg•d) for 4 weeks] and huperzine A group [AD rats treated with huperzine A at the dosage of 40.5 µg/(kg•d) for 4 weeks]. Spatial learning and memory level was detected by Morris Water Maze test. Histological morphology in the hippocampus was tested by hematoxylin-eosin (HE) staining. Cyclin-dependent kinase-5 (Cdk5) protein and gene expression level were investigated by Western blot analysis and real-time quantitative polymerase chain reaction (RT-qPCR), respectively. RESULTS: Aß1-40 and IBO treatment induced longer escape latency of rats, compared with sham operation group from day 25 (P<0.01). However, TYD and huperzine A obviously shortened the escape latency from day 26 (P<0.01). Moreover, the effect of TYD was similar to huperzine A (P>0.05). Furthermore, HE staining also showed that TYD and huperzine A reversed the neuropathological changes in the hippocampus triggered by Aß1-40 and IBO. TYD and huperzine A effectively reduced the expression levels of Cdk5 protein and gene located in rat hippocampus, compared with the AD model group (P<0.01). CONCLUSION: TYD could be a promising neuroprotective agent for protecting neuron from AD injury through inhibiting Cdk5 expression.

Role of dihydrofolate reductase in tetrahydrobiopterin biosynthesis and lipid metabolism in the oleaginous fungus Mortierella alpina.

Mortierella alpina is a well-known polyunsaturated fatty acid-producing oleaginous fungus. Analysis of the Mort. alpina genome suggests that there is a putative dihydrofolate reductase (DHFR) gene playing a role in the salvage pathway of tetrahydrobiopterin (BH4), which has never been explored in fungi before. DHFR is the sole source of tetrahydrofolate and plays a key role in maintaining BH4 levels. Transcriptome data analysis revealed that DHFR was up-regulated by nitrogen exhaustion, when Mort. alpina starts to accumulate lipids. Significant changes were found in the fatty acid profile in Mort. alpina grown on medium containing DHFR inhibitors compared to Mort. alpina grown on medium without inhibitors. To explore the role of DHFR in folate/BH4 metabolism and its relationship to lipid biosynthesis, we expressed heterologously the gene encoding DHFR from Mort. alpina in Escherichia coli and we purified the recombinant enzyme to homogeneity. The enzymatic activity was investigated by liquid chromatography and MS and VIS-UV spectroscopy. The kinetic parameters and the effects of temperature, pH, metal ions and inhibitors on the activity of DHFR were also investigated. The transcript level of cytosolic NADPH-producing gene involved in folate metabolism is down-regulated by DHFR inhibitors, which highlights the functional significance of DHFR in lipid biosynthesis. The relationship between DHFR and lipid metabolism is thus of major importance, and folate metabolism may be an alternative NADPH source in fatty acid synthesis. To our knowledge, this study is the first to report the comprehensive characterization of a BH4salvage pathway in a fungus.

Role of aeration intensity on performance and microbial community profiles in a sequencing batch reaction kettle (SBRK) for wastewater nutrients rapid removal.

A lab-scale SBRK was operated to investigate the effects of aeration intensity on the system performance and microbial community dynamics within it. Results showed that the sewage nutrients was removed rapidly (just about 3-6h) with the aeration intensity increasing from 0 to 0.6MPa. Average effluent parameters were: COD below 50mg/L, NH4(+)-N less than 1mg/L, 1.5-4.5mg/L for nitrate and TP below 0.5mg/L. The highest community similarity and diversity emerged simultaneously with the aeration pressure rising from 0.2 to 0.4MPa, which was regarded as the optimal aeration intensity range. Microbial community shifted obviously and the function species of Comamonadaceae, Dechloromonas, Flavobacterium and Nitrospira dominated in the corresponding communities. RDA indicated that aeration intensity was the main factor for regulating system communities to optimize the system performance. It inferred that high aeration pressure played a key role on sewage nutrients rapid removal.

Peroxynitrite Decomposition Catalyst Reduces Delayed Thrombolysis-induced Hemorrhagic Transformation in Ischemia-reperfused Rat Brains.

AIM: Hemorrhagic transformation (HT) is a major complication of delayed tissue plasminogen activator (t-PA) treatment in ischemic stroke. We aimed to explore whether peroxynitrite decomposition catalyst (PDC) could prevent such complication. METHODS: Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) with t-PA (10 mg/kg) or t-PA plus FeTMPyP (3 mg/kg, a representative PDC) at MCAO for 2 or 5 h and reperfusion for 22 or 19 h, respectively. HT was assessed with hemoglobin assay. Neurological deficit was evaluated with Modified Neurological Severity Score (mNSS). Peroxynitrite formation was examined by detecting 3-nitrotyrosine (3-NT) formation. The expression and activity of MMP-9/MMP-2 were assessed by Western blotting and gelatin zymography. RESULTS: t-PA treatment at 2 h of MCAO did not induce HT but attenuated neurological deficit, whereas treatment at 5 h significantly induced HT and worsened the neurological outcome. Such complications were prevented by FeTMPyP cotreatment. Early t-PA treatment inhibited 3-NT and MMP-9/MMP-2 expression, whereas delayed treatment induced 3-NT and MMP-9/MMP-2 expression and activity. FeTMPyP cotreatment downregulated 3-NT and inhibited MMP-9/MMP-2 in both time points. CONCLUSION: Peroxynitrite decomposition catalyst could prevent hemorrhagic transformation and improve neurological outcome ischemic rat brains with delayed t-PA treatment via inhibiting peroxynitrite-mediated MMP activation.