Publications by authors named "Xiaolei Zhu"

217 Publications

Alterations in circulating extracellular vesicles underlie social stress-induced behaviors in mice.

FEBS Open Bio 2021 May 27. Epub 2021 May 27.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Chronic stress induces peripheral and intracerebral immune changes and inflammation, contributing to neuropathology and behavioral abnormalities relevant to psychiatric disorders such as depression. Although the pathological implication of many peripheral factors such as pro-inflammatory cytokines, hormones, and macrophages has been demonstrated, the roles of circulating extracellular vesicles (EVs) for chronic stress mechanisms remain poorly investigated. Here we report that chronic social defeat stress (CSDS)-induced social avoidance phenotype, assessed by a previously untested three-chamber social approach test, can be distinguished by multiple pro-inflammatory cytokines and EV-associated molecular signatures in the blood. We found that the expression patterns of miRNAs distinguished the CSDS-susceptible mice from the CSDS-resilient mice. Social avoidance behavior scores were also estimated with good accuracy by the expression patterns of multiple EV-associated miRNAs. We also demonstrated that EVs enriched from the CSDS-susceptible mouse sera upregulated the production of pro-inflammatory cytokines in the LPS-stimulated microglia-like cell lines. Our results indicate the role of circulating EVs and associated miRNAs in CSDS susceptibility, which may be related to pro-inflammatory mechanisms underlying stress-induced neurobehavioral outcomes.
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http://dx.doi.org/10.1002/2211-5463.13204DOI Listing
May 2021

Causal impact of local inflammation in the nasal cavity on higher brain function and cognition.

Neurosci Res 2021 Apr 28. Epub 2021 Apr 28.

Department of Psychiatry, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA. Electronic address:

Epidemiological evidence suggests that adverse environmental factors in the nasal cavity may increase the risk for neuropsychiatric diseases. For instance, air pollution and nasal viral infection have been underscored as risk factors for Parkinson's disease, schizophrenia, and mood disorders. These adverse factors can elicit local inflammation in the nasal cavity, which may in turn influence higher brain function. Nevertheless, evidence that directly supports their causal link is missing. To fill this knowledge gap, we used an inducible mouse model for olfactory inflammation and showed the evidence that this local pathological factor can elicit behavioral abnormalities.
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http://dx.doi.org/10.1016/j.neures.2021.04.009DOI Listing
April 2021

Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis.

Mol Ther 2021 Apr 23. Epub 2021 Apr 23.

Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210008, P.R. China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, P.R. China; Nanjing Neurology Clinic Medical Center, Nanjing, Jiangsu 210008, P.R. China. Electronic address:

Dysregulated long non-coding RNAs (lncRNAs) have been shown to contribute to the pathogenesis of ischemic stroke. However, the potential role of lncRNAs in post-stroke microglial activation remains largely unknown. Here, we uncovered that lncRNA-U90926 was significantly increased in microglia exposed to ischemia/reperfusion both in vivo and in vitro. In addition, adenovirus-associated virus (AAV)-mediated microglial U90926 silencing alleviated neurological deficits and reduced infarct volume in experimental stroke mice. Microglial U90926 knockdown could reduce the infiltration of neutrophils into ischemic lesion site, which might be attributed to the downregulation of C-X-C motif ligand 2 (CXCL2). Mechanistically, U90926 directly bound to malate dehydrogenase 2 (MDH2) and competitively inhibited the binding of MDH2 to the CXCL2 3' untranslated region (UTR), thus protecting against MDH2-mediated decay of CXCL2 mRNA. Taken together, our study demonstrated that microglial U90926 aggravated ischemic brain injury via facilitating neutrophil infiltration, suggesting that U90926 might be a potential biomarker and therapeutic target for ischemic stroke.
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http://dx.doi.org/10.1016/j.ymthe.2021.04.025DOI Listing
April 2021

Mapping C-H⋅⋅⋅M Interactions in Confined Spaces: (α-ICyD )Au, Ag, Cu Complexes Reveal "Contra-electrostatic H Bonds" Masquerading as Anagostic Interactions*.

Chemistry 2021 Jun 6;27(31):8127-8142. Epub 2021 May 6.

Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 place Jussieu, 75005, Paris, France.

What happens when a C-H bond is forced to interact with unpaired pairs of electrons at a positively charged metal? Such interactions can be considered as "contra-electrostatic" H-bonds, which combine the familiar orbital interaction pattern characteristic for the covalent contribution to the conventional H-bonding with an unusual contra-electrostatic component. While electrostatics is strongly stabilizing component in the conventional C-H⋅⋅⋅X bonds where X is an electronegative main group element, it is destabilizing in the C-H⋅⋅⋅M contacts when M is Au(I), Ag(I), or Cu(I) of NHC-M-Cl systems. Such remarkable C-H⋅⋅⋅M interaction became experimentally accessible within (α-ICyD )MCl, NHC-Metal complexes embedded into cyclodextrins. Computational analysis of the model systems suggests that the overall interaction energies are relatively insensitive to moderate variations in the directionality of interaction between a C-H bond and the metal center, indicating stereoelectronic promiscuity of fully filled set of d-orbitals. A combination of experimental and computational data demonstrates that metal encapsulation inside the cyclodextrin cavity forces the C-H bond to point toward the metal, and reveals a still attractive "contra-electrostatic" H-bonding interaction.
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http://dx.doi.org/10.1002/chem.202100263DOI Listing
June 2021

Exosomal MicroRNAs Contribute to Cognitive Impairment in Hypertensive Patients by Decreasing Frontal Cerebrovascular Reactivity.

Front Neurosci 2021 1;15:614220. Epub 2021 Mar 1.

The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Medical School, Drum Tower Hospital, Institute of Brain Science, Nanjing University, Nanjing, China.

Mechanisms underlying cognitive impairment (CI) in hypertensive patients remain relatively unclear. The present study aimed to explore the relationship among serum exosomal microRNAs (miRNAs), cerebrovascular reactivity (CVR), and cognitive function in hypertensive patients. Seventy-three hypertensive patients with CI (HT-CI), 67 hypertensive patients with normal cognition (HT-NC), and 37 healthy controls underwent identification of exosomal miRNA, multimodal magnetic resonance imaging (MRI) scans, and neuropsychological tests. CVR mapping was investigated based on resting-state functional MRI data. Compared with healthy subjects and HT-NC subjects, HT-CI subjects displayed decreased serum exosomal miRNA-330-3p. The group difference of CVR was mainly found in the left frontal lobe and demonstrated that HT-CI group had a lower CVR than both HT-NC group and control group. Furthermore, both the CVR in the left medial superior frontal gyrus and the miRNA-330-3p level were significantly correlated with executive function ( = -0.275, = 0.021, and = -0.246, = 0.04, respectively) in HT-CI subjects, and the CVR was significantly correlated with the miRNA-330-3p level ( = 0.246, = 0.040). Notably, path analysis showed that the CVR mediated the association between miRNA-330-3p and executive function. In conclusion, decreased miRNA-330-3p might contribute to CI in hypertensive patients by decreasing frontal CVR and could be a biomarker of early diagnosis.
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http://dx.doi.org/10.3389/fnins.2021.614220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957933PMC
March 2021

n-3 PUFAs protect against adiposity and fatty liver by promoting browning in postnatally overfed male rats: a role for NRG4.

J Nutr Biochem 2021 Jul 8;93:108628. Epub 2021 Mar 8.

Department of Child Health Care, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Institute of Pediatric Research, Nanjing Medical University, Nanjing, Jiangsu Province, China. Electronic address:

Early-life nutrition plays an important role in regulating adult metabolism. This study evaluated the effects of early nutrition during the suckling and postweaning periods on expression of the adipocytokine Neuregulin 4 (Nrg4) and its relationship with nonalcoholic fatty liver disease (NAFLD) in adulthood. In vivo, male rats were adjusted to litter sizes of three (small litter, SL) or ten (normal litter, NL) on postnatal day 3. Pups were fed control chow (NL and SL groups) or a high-fat diet (NL-HF and SL-HF groups), and SL pups specifically were fed a fish oil diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs) (SL-FO group), from postnatal weeks 3 to 13. The results demonstrated that postnatal overnutrition increased weight, hepatic de novo lipogenesis (DNL) gene expression and NAFLD and decreased body temperature and Nrg4, Ucp1 and Pgc1a mRNA expression in adipose tissues in SL, SL-HF and NL-HF rats compared to NL rats in adulthood. The opposite trends were observed in SL-FO rats. Moreover, in vitro, recombinant NRG4 protein reduced lipid accumulation by inhibiting DNL gene expression in fatty HepG2 cells stimulated with sodium oleate. In HPAs, eicosapentaenoic acid (EPA) treatment elevated NRG4 production and caused adipocyte browning, and these effects were abrogated by PPARG antagonism. In conclusion, a postweaning n-3 PUFA diet enhanced Nrg4 expression in adipose tissues, associated with attenuation of NAFLD induced by SL rearing. Additionally, external NRG4 reduced lipogenesis in steatotic hepatocytes. Thus, white adipose tissue browning induced by n-3 PUFAs may promote NRG4 production through the PPARG pathway.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108628DOI Listing
July 2021

Nitromethane Decomposition via Automated Reaction Discovery and an Corrected Kinetic Model.

J Phys Chem A 2021 Feb 11;125(7):1447-1460. Epub 2021 Feb 11.

Department of Chemistry and The PULSE Institute, Stanford University, Stanford, California 94305, United States.

We explore the systematic construction of kinetic models from reaction data for the decomposition of nitromethane. Our models are constructed in a computationally affordable manner by using reactions discovered through accelerated molecular dynamics simulations using the ReaxFF reactive force field. The reaction paths are then optimized to determine reaction rate parameters. We introduce a reaction barrier correction scheme that combines accurate thermochemical data from density functional theory with ReaxFF minimal energy paths. We validate our models across different thermodynamic regimes, showing predictions of gas phase CO and NO concentrations and high-pressure induction times that are similar to experimental data. The kinetic models are analyzed to find fundamental decomposition reactions in different thermodynamic regimes.
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http://dx.doi.org/10.1021/acs.jpca.0c09168DOI Listing
February 2021

Early Segmental White Matter Fascicle Microstructural Damage Predicts the Corresponding Cognitive Domain Impairment in Cerebral Small Vessel Disease Patients by Automated Fiber Quantification.

Front Aging Neurosci 2020 11;12:598242. Epub 2021 Jan 11.

Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China.

To characterize earlier damage pattern of white matter (WM) microstructure in cerebral small vessel disease (CSVD) and its relationship with cognitive domain dysfunction. A total of 144 CSVD patients and 100 healthy controls who underwent neuropsychological measurements and diffusion tensor imaging (DTI) examination were recruited. Cognitive function, emotion, and gait were assessed in each participant. The automated fiber quantification (AFQ) technique was used to extract different fiber properties between groups, and partial correlation and general linear regression analyses were performed to assess the relationship between position-specific WM microstructure and cognitive function. Specific segments in the association fibers, commissural WM regions of interest (ROIs), and projection fibers were damaged in the CSVD group [ < 0.05, family-wise error (FWE) correction], and these damaged segments showed interhemispheric symmetry. In addition, the damage to specific tract profiles [including the posteromedial component of the right cingulum cingulate (CC), the occipital lobe portion of the callosum forceps major, the posterior portion of the left superior longitudinal fasciculus (SLF), and the bilateral anterior thalamic radiation (ATR)] was related to the dysfunction in specific cognitive domains. Among these tracts, we found the ATR to be the key set of tracts whose profiles were most associated with cognitive dysfunction. The left ATR was a specific fiber bundle associated with episode memory and language function, whereas the fractional anisotropy (FA) values of the intermediate component of the right ATR were negatively correlated with executive function and gait evaluation. It should be noted that the abovementioned relationships could not survive the Bonferroni correction ( < 0.05/27), so we chose more liberal uncorrected statistical thresholds. Damage to the WM fiber bundles showed extensive interhemispheric symmetry and was limited to particular segments in CSVD patients. Disruption of strategically located fibers was associated with different cognitive deficits, especially the bilateral ATR.
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http://dx.doi.org/10.3389/fnagi.2020.598242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829360PMC
January 2021

Photoactive Organic/Inorganic Hybrid Materials with Nanosegregated Donor-Acceptor Arrays.

Angew Chem Int Ed Engl 2021 Apr 5;60(15):8419-8424. Epub 2021 Mar 5.

Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, IPCM, 4 Place Jussieu, 75005, Paris, France.

The synthesis of the first mesogenic donor-acceptor polyoxometalate (POM)-based hybrid is herein described. The structural and electronic properties of the hybrid compound were evaluated through combination of small- and wide-angle X-ray scattering, optical microscopy, electrochemistry and photoluminescence. In the solid state, the compound behaves as a birefringent solid, displaying a lamellar organization in which double-layers of POMs and bis(thiophene)thienothiophene organic donors alternate regularly. Noticeably, the sub-unit organizations in the composite are similar to that observed for the individual POM and organic donor precursors. Photophysical studies show that in the hybrid, the fluorescence of the organic donor unit is considerably quenched both in solution and in the solid state, which is attributed to occurrence of intramolecular charge-separated state.
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http://dx.doi.org/10.1002/anie.202014319DOI Listing
April 2021

Carbon deposition enhanced selective catalytic reduction of nitric oxide by a new catalytic process as well as increasing reducibility of catalyst.

Sci Total Environ 2021 Feb 20;756:143834. Epub 2020 Nov 20.

SHU Center of Green Urban Mining & Industry Ecology, School of Environmental and Chemical Engineering, Shanghai University, No. 381 Nanchen Road, Shanghai 200444, PR China. Electronic address:

Carbon deposition usually hinders catalytic activity in one catalysis. In this work, carbon-deposition influence was investigated on selective catalytic reduction (SCR) of nitric oxide (NO) by a theoretical-experimental method. Density-functional-theory calculations showed that carbon deposition increased adsorption energy of NO on oxide. For example, adsorption energy on FeO increased from 1.70 to 5.27 eV. Carbon deposition increased activity by following processes: NO adsorption, NO dissociation, oxygen transmittance, CO-group formation, and N/CO evolutions. Among these stages, CO-group formation was a key step. Based on these computational predictions, an experimental SCR was carried out for the verification. As a result, a carbon-deposited catalyst had a better SCR activity (20% higher) than the corresponding oxide catalyst. Characterizations showed that carbon deposition increased the amounts of medium/strong acidic sites as well as the reducibility of the catalytic center. The main result of this article helps to understand the interface behavior of carbon on a catalyst during SCR. Above results are also in favor of designing a more effective SCR reactor to ensure a more stable running.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143834DOI Listing
February 2021

m5CPred-SVM: a novel method for predicting m5C sites of RNA.

BMC Bioinformatics 2020 Oct 30;21(1):489. Epub 2020 Oct 30.

School of Sciences, Anhui Agricultural University, Hefei, 230036, Anhui, China.

Background: As one of the most common post-transcriptional modifications (PTCM) in RNA, 5-cytosine-methylation plays important roles in many biological functions such as RNA metabolism and cell fate decision. Through accurate identification of 5-methylcytosine (m5C) sites on RNA, researchers can better understand the exact role of 5-cytosine-methylation in these biological functions. In recent years, computational methods of predicting m5C sites have attracted lots of interests because of its efficiency and low-cost. However, both the accuracy and efficiency of these methods are not satisfactory yet and need further improvement.

Results: In this work, we have developed a new computational method, m5CPred-SVM, to identify m5C sites in three species, H. sapiens, M. musculus and A. thaliana. To build this model, we first collected benchmark datasets following three recently published methods. Then, six types of sequence-based features were generated based on RNA segments and the sequential forward feature selection strategy was used to obtain the optimal feature subset. After that, the performance of models based on different learning algorithms were compared, and the model based on the support vector machine provided the highest prediction accuracy. Finally, our proposed method, m5CPred-SVM was compared with several existing methods, and the result showed that m5CPred-SVM offered substantially higher prediction accuracy than previously published methods. It is expected that our method, m5CPred-SVM, can become a useful tool for accurate identification of m5C sites.

Conclusion: In this study, by introducing position-specific propensity related features, we built a new model, m5CPred-SVM, to predict RNA m5C sites of three different species. The result shows that our model outperformed the existing state-of-art models. Our model is available for users through a web server at https://zhulab.ahu.edu.cn/m5CPred-SVM .
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http://dx.doi.org/10.1186/s12859-020-03828-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602301PMC
October 2020

Survival analysis of patients with primary gallbladder cancer from 2010 to 2015: A retrospective study based on SEER data.

Medicine (Baltimore) 2020 Oct;99(40):e22292

National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing.

This study aims to assess the survival status of patients with Primary gallbladder cancer (PGC) and analyze the prognosis factors to facilitate the exploration of the prevention and therapeutic strategies of PGC.Data from 2433 PGC patients collected from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The SEER*Stat, SPSS 23.0 and GraphPad Prism 8 were used for statistical analyses. Kaplan Meier analysis was performed for the survival curve, log-rank test analyses were used to compare the survival rate difference and Cox regression analyses were performed to determine the prognosis factors.A total of 2433 PGC cases were reported from 2010 to 2015. The median age was 64.2 ± 10.4 years old and the percentages of the white patients were 73.7% (1794/2433). The percentage of patients who received surgery treatment was 82.1% (1998/2433). The overall median survival time of all patients was 19 months and the 5-year survival rate was 28.8%. The 5-year survival rate of PGC patients in pN2 stage dropped to 0% and the 5-year survival rate for PGC patients with distant metastasis was only 2.7%. Age, tumor size, grade, pT stage, pM stage were risk factors for prognosis, surgery or not and radiation or not were protective factors for prognosis.Survival analysis of PGC patients based on the SEER database have provided an opportunity for understanding PGC prognosis and the basis for the exploration of viable PGC prevention and therapeutic strategies.
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http://dx.doi.org/10.1097/MD.0000000000022292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535694PMC
October 2020

miR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer's Disease.

Mol Ther 2021 01 5;29(1):396-408. Epub 2020 Sep 5.

Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210093, PR China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, PR China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, PR China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu 210008, PR China; Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, Jiangsu 211166, PR China. Electronic address:

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly, and the mechanisms of AD are not fully defined. MicroRNAs (miRNAs) have been shown to contribute to memory deficits in AD. In this study, we identified that miR-204-3p was downregulated in the hippocampus and plasma of 6-month-old APPswe/PS1dE9 (APP/PS1) mice. miR-204-3p overexpression attenuated memory and synaptic deficits in APP/PS1 mice. The amyloid levels and oxidative stress were decreased in the hippocampus of APP/PS1 mice after miR-204-3p overexpression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) was a target of miR-204-3p, and Nox4 inhibition by GLX351322 protected neuronal cells against Aβ-induced neurotoxicity. Furthermore, GLX351322 treatment rescued synaptic and memory deficits, and decreased oxidative stress and amyloid levels in the hippocampus of APP/PS1 mice. These results revealed that miR-204-3p attenuated memory deficits and oxidative stress in APP/PS1 mice by targeting Nox4, and miR-204-3p overexpression and/or Nox4 inhibition might be a potential therapeutic strategy for AD treatment.
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http://dx.doi.org/10.1016/j.ymthe.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791017PMC
January 2021

Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice.

J Alzheimers Dis 2020 ;77(1):437-447

Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.

Background: Given the emergent aging population, the identification of effective treatments for Alzheimer's disease (AD) is critical.

Objective: We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model.

Methods: Cell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4-5 months and cognitive performance was assessed using the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083.

Results: JHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings,postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment.

Conclusion: These results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD.
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http://dx.doi.org/10.3233/JAD-190588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678030PMC
January 2020

iPNHOT: a knowledge-based approach for identifying protein-nucleic acid interaction hot spots.

BMC Bioinformatics 2020 Jul 6;21(1):289. Epub 2020 Jul 6.

Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, USA.

Background: The interaction between proteins and nucleic acids plays pivotal roles in various biological processes such as transcription, translation, and gene regulation. Hot spots are a small set of residues that contribute most to the binding affinity of a protein-nucleic acid interaction. Compared to the extensive studies of the hot spots on protein-protein interfaces, the hot spot residues within protein-nucleic acids interfaces remain less well-studied, in part because mutagenesis data for protein-nucleic acids interaction are not as abundant as that for protein-protein interactions.

Results: In this study, we built a new computational model, iPNHOT, to effectively predict hot spot residues on protein-nucleic acids interfaces. One training data set and an independent test set were collected from dbAMEPNI and some recent literature, respectively. To build our model, we generated 97 different sequential and structural features and used a two-step strategy to select the relevant features. The final model was built based only on 7 features using a support vector machine (SVM). The features include two unique features such as ∆SASsa and esp3, which are newly proposed in this study. Based on the cross validation results, our model gave F1 score and AUROC as 0.725 and 0.807 on the subset collected from ProNIT, respectively, compared to 0.407 and 0.670 of mCSM-NA, a state-of-the art model to predict the thermodynamic effects of protein-nucleic acid interaction. The iPNHOT model was further tested on the independent test set, which showed that our model outperformed other methods.

Conclusion: In this study, by collecting data from a recently published database dbAMEPNI, we proposed a new model, iPNHOT, to predict hotspots on both protein-DNA and protein-RNA interfaces. The results show that our model outperforms the existing state-of-art models. Our model is available for users through a webserver: http://zhulab.ahu.edu.cn/iPNHOT/ .
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http://dx.doi.org/10.1186/s12859-020-03636-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336410PMC
July 2020

Muscone Ameliorates Synaptic Dysfunction and Cognitive Deficits in APP/PS1 Mice.

J Alzheimers Dis 2020 ;76(2):491-504

Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China.

Background: Dysfunction of synaptic plasticity leads to memory impairment in Alzheimer's disease (AD). Muscone (Mus) has shown neuroprotective effects in cerebral ischemic models. However, little is known of Mus effects on AD.

Objective: To investigate the effects of Mus on memory functions and synaptic plasticity in 6-month-old APP/PS1 double-transgenic mice and explore the potential mechanisms.

Methods: Mus was intraperitoneally injected into APP/PS1 or wild-type mice, and cognitive function was assessed by Novel object recognition and Morris water maze tests. The levels of amyloid-β (Aβ) were evaluated by immunofluorescence staining and ELISA. Synaptic morphology and plasticity were evaluated by Golgi staining and long-term potentiation. Cell viability was examined by Cell Counting Kit-8 assay. The protein levels of histone deacetylase 2 (HDAC2) were accessed by western blotting and Immunofluorescence staining. The protein levels of microtubule associated protein 2 and synaptophysin were analyzed by immunofluorescence staining. The ubiquitination of HDAC2 was examined by co-immunoprecipitation. The interaction of Mus with HDAC2 was predicted by molecular docking analysis.

Results: Mus treatment attenuated memory dysfunction, reduced Aβ level, and enhanced synaptic plasticity in APP/PS1 mice. In addition, Mus treatment decreased the level of HDAC2 in the hippocampus of APP/PS1 mice and Aβ1-42-induced primary neurons, which might be associated with increased HDAC2 ubiquitination induced by HDAC2 and Mus interaction.

Conclusion: Mus protected against synaptic plasticity and memory impairment in APP/PS1 mice, and enhanced HDAC2 degradation via ubiquitination, indicating that Mus was a potential drug for AD treatment.
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http://dx.doi.org/10.3233/JAD-200188DOI Listing
May 2021

Permethylated NHC-Capped α- and β-Cyclodextrins (ICyD ) Regioselective and Enantioselective Gold-Catalysis in Pure Water.

Chemistry 2020 Dec 7;26(68):15901-15909. Epub 2020 Oct 7.

Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4, place Jussieu, 75005, Paris, France.

A series of water-soluble encapsulated copper(I), silver(I) or gold(I) complexes based on NHC-capped permethylated cyclodextrins (ICyD ) were developed and used as catalysts in pure water for hydration, lactonization, hydroarylation and cycloisomerization reactions. ICyD ligands gave cavity-based high regioselectivity in hydroarylations, and high enantioselectivities in gold-catalyzed cycloisomerizations reactions giving up to 98 % ee in water. These ICyD are therefore useful ligands for selective catalysis in pure water.
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http://dx.doi.org/10.1002/chem.202001990DOI Listing
December 2020

Xingnaojing ameliorates synaptic plasticity and memory deficits in an Aβ induced mouse model of Alzheimer's disease.

J Pharmacol Sci 2020 Aug 14;143(4):245-254. Epub 2020 May 14.

Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China; Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China. Electronic address:

The accumulation of insoluble amyloid β (Aβ) peptides is one of the pathological changes in Alzheimer's disease (AD), which induced synaptic plasticity impairment and excitatory amino acid toxicity associated with decreased memory function. Xingnaojing (XNJ), a well-known prescription in traditional Chinese medicine, has been used for the treatment of stroke for many years in China. In this study, we aim to investigate the therapeutic effects of XNJ in a hippocampus of Aβ induced mouse model of AD which showed significant memory loss and impaired synaptic morphology and function. Treatment of XNJ could attenuate spatial and working memory dysfunction, increase dendritic spine density and improve long-term potential (LTP) induction. In addition, XNJ treatment significantly increased the level of N-methyl-d-aspartate receptors (NMDARs) and inhibit the NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) ratio in AD mice. XNJ treatment also activated the AKT/mechanistic target of rapamycin (mTOR) pathway, while inhibition of the mTOR pathway by rapamycin could reverse the protective effects of XNJ treatment. In conclusion, XNJ protected against synaptic plasticity and memory impairment in AD mice via the activation of AKT/mTOR signaling pathway, suggesting XNJ as an alternative treatment for AD.
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http://dx.doi.org/10.1016/j.jphs.2020.05.002DOI Listing
August 2020

Simultaneous observation of nuclear and electronic dynamics by ultrafast electron diffraction.

Science 2020 05;368(6493):885-889

SLAC National Accelerator Laboratory, Menlo Park, CA, USA.

Simultaneous observation of nuclear and electronic motion is crucial for a complete understanding of molecular dynamics in excited electronic states. It is challenging for a single experiment to independently follow both electronic and nuclear dynamics at the same time. Here we show that ultrafast electron diffraction can be used to simultaneously record both electronic and nuclear dynamics in isolated pyridine molecules, naturally disentangling the two components. Electronic state changes (S→S internal conversion) were reflected by a strong transient signal in small-angle inelastic scattering, and nuclear structural changes (ring puckering) were monitored by large-angle elastic diffraction. Supported by ab initio nonadiabatic molecular dynamics and diffraction simulations, our experiment provides a clear view of the interplay between electronic and nuclear dynamics of the photoexcited pyridine molecule.
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http://dx.doi.org/10.1126/science.abb2235DOI Listing
May 2020

Strictly non-adiabatic quantum control of the acetylene dication using an infrared field.

J Chem Phys 2020 May;152(18):184302

Stanford PULSE Institute, SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, California 94025, USA.

We demonstrate the existence of a strictly non-adiabatic control pathway in deprotonation of the acetylene dication. This pathway is identified experimentally by measuring a kinetic energy shift in an ion coincidence experiment. We use a time dependent Schrödinger equation simulation to identify which properties most strongly affect our control. We find that resonant control around conical intersections is limited by the speed of non-adiabatic dynamics.
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http://dx.doi.org/10.1063/5.0007058DOI Listing
May 2020

Compact dual-wavelength blue-green laser for airborne ocean detection lidar.

Appl Opt 2020 Apr;59(10):C87-C91

We have demonstrated a dual-wavelength blue-green laser for airborne ocean lidar based on an all-solid-state master oscillator power amplifier and nonlinear frequency conversion methods. A -switched pulsed laser with 10 mJ energy at 1064 nm was amplified to 108 mJ by a Nd:YAG amplifier side pumped by vertical-cavity surface-emitting laser modules. This fundamental laser was then frequency tripled to 355 nm wavelength by lithium triborate (LBO) crystals. With maximum pump energy of 43.5 mJ at 355 nm, 9.6 mJ of blue laser pulse at 486.1 nm was successfully obtained from an optical parametric oscillator unit using two beta-barium borate crystals. The energy of the residual 532 nm laser pulse was 10.6 mJ. Equipped with this laser system, an airborne blue-green lidar was developed, and ocean detection was carried out in the South China Sea, where an optical vertical profile at seawater depth of 94 m was obtained.
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http://dx.doi.org/10.1364/AO.382174DOI Listing
April 2020

Combined quantitative evaluation on early-stage fatigue damage of coarse-grained austenite stainless steel based on EBSD and ultrasonic technique.

Ultrasonics 2020 Apr 30;103:106090. Epub 2020 Jan 30.

NDT & E Laboratory, Dalian University of Technology, Dalian 116085, China. Electronic address:

The elastic anisotropy and heterogeneity effects of coarse-grained austenite on ultrasonic propagation significantly undermine the effectiveness of ultrasonic property-based fatigue damage evaluation. A discrete method based on electron backscatter diffraction (EBSD) was proposed to decouple the effects between coarse-grained structure and fatigue damage. An orientation-based damage index, local misorientation (M), was extracted and macroscopic and microscopic plastic deformations were characterized. The evolution of ultrasonic attenuation coefficient Δα was established with ΔM in grain scale. Approximate downward parabolas was observed, and the peak value of Δα in 〈1 1 1〉 orientation was found to be larger and more sensitive to the cyclic damage than that of 〈0 0 1〉 and 〈0 1 1〉. The influences of the heterogeneous substructure and surface roughness were discussed respectively.
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http://dx.doi.org/10.1016/j.ultras.2020.106090DOI Listing
April 2020

Differences in Neuregulin 4 Expression in Children: Effects of Fat Depots and Obese Status.

Endocr Res 2020 Aug 27;45(3):190-201. Epub 2020 Jan 27.

Department of Children Health Care, Children's Hospital of Nanjing Medical University , Nanjing, China.

Purpose: To observe the expression of Nrg4, uncoupling protein-1 (UCP1), tumor necrosis factor α (TNFα), CD31, VE-cadherin/CDH5 and vascular endothelial growth factor A (VEGF-A) mRNA in abdominal subcutaneous (SC), omental (OM) adipose tissue in children with relation to anthropometric parameters. Further to verify the effect of inflammatory mediators on Nrg4 and UCP1 mRNA expression in adipocytes.

Methods: Paired SC and OM adipose tissues were obtained from 58 children. In vitro, the adipocytes isolated from primary inguinal adipose tissue of mice were treated with TNFα (50 ng/ml) for 12-48 h. mRNA levels of Nrg4, UCP1 and TNFα were determined by real-time PCR.

Results: Nrg4, UCP1, VEGF-A and CDH5 mRNA levels in SC were significantly higher than those in OM adipose tissue and the mRNA level of TNFα showed the opposite result. Moreover, Nrg4 and UCP1 mRNA in SC were significantly lower in overweight children compared to normal weight children. Nrg4 in SC and OM was negatively associated with BMISDS, WHtR. CDH55 mRNA in OM was negatively associated with WHR. VEGF-A was positively correlated with Nrg4 in SC. In vitro, Nrg4 and UCP1 mRNA levels in adipocytes were dose- and time-dependently decreased under TNFα treatment.

Conclusions: Nrg4, UCP1, VEGF-A and CDH5 mRNA expression in adipose tissues display a depot-specific pattern. Nrg4 mRNA levels in adipose tissue are decreased with obesity and associated with WAT browning and angiogenesis. TNFα may be involved in the regulation of Nrg4 level in adipose tissue, which may be one of the causes of the down-regulation of Nrg4 expression in obesity with chronic inflammatory response.
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http://dx.doi.org/10.1080/07435800.2020.1721528DOI Listing
August 2020

The efficacy of gray matter atrophy and cognitive assessment in differentiation of aMCI and naMCI.

Appl Neuropsychol Adult 2020 Jan 16:1-7. Epub 2020 Jan 16.

Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China.

Mild cognitive impairment (MCI) is a heterogeneous entity that can be categorized into related but different subtypes. In this study, we analyzed the gray matter structural changes of amnestic MCI (aMCI) and non-amnestic MCI (naMCI), and how it resulted in diverse cognitive impairment. Altogether 77 individuals were recruited, including 28 cognitively normal controls (NC), 25 naMCI subjects, and 24 aMCI subjects. All participants underwent a 3.0 T magnetic resonance (MR) scan and a detailed neuropsychological examination. Cortical thickness and subcortical nuclei volume were extracted by Freesurfer software and compared among groups. The areas with significant differences were further analyzed by general linear regression to identify the risk factors of each cognitive impairment subtypes. Significant differences were observed in bilateral hippocampi, amygdala, thalamus, accumbens, left transverse temporal gyrus and left precuneus among groups. AMCI and naMCI were significantly different in the right hippocampus, bilateral amygdala, left precuneus, and left transverse temporal gyrus. Linear regression analysis revealed that the atrophy of left precuneus was a risk factor of memory, executive function (EF) and visuospatial impairment ( < 0.001). The atrophy of left amygdala, right accumbens and left thalamus were risk factors of memory, EF and language impairment respectively ( < 0.05). These findings confirmed that different gray matter structural changes could lead to specific neuropsychological features in MCI subtypes. Thorough understanding of MCI subtypes and the underlying pathology would be beneficial for precise diagnosis and intervention.
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http://dx.doi.org/10.1080/23279095.2019.1710509DOI Listing
January 2020

The cascade unzipping of ladderane reveals dynamic effects in mechanochemistry.

Nat Chem 2020 03 6;12(3):302-309. Epub 2020 Jan 6.

Department of Chemistry and Stanford University, Stanford, CA, USA.

Force can induce remarkable non-destructive transformations along a polymer, but we have a limited understanding of the energy transduction and product distribution in tandem mechanochemical reactions. Ladderanes consist of multiple fused cyclobutane rings and have recently been used as monomeric motifs to develop polymers that drastically change their properties in response to force. Here we show that [4]-ladderane always exhibits 'all-or-none' cascade mechanoactivations and the same stereochemical distribution of the generated dienes under various conditions and within different polymer backbones. Transition state theory fails to capture the reaction kinetics and explain the observed stereochemical distributions. Ab initio steered molecular dynamics reveals unique non-equilibrium dynamic effects: energy transduction from the first cycloreversion substantially accelerates the second cycloreversion, and bifurcation on the force-modified potential energy surface leads to the product distributions. Our findings illustrate the rich chemistry in closely coupled multi-mechanophores and an exciting potential for effective energy transduction in tandem mechanochemical reactions.
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http://dx.doi.org/10.1038/s41557-019-0396-5DOI Listing
March 2020

miR-512-5p suppresses the progression of non-small cell lung cancer by targeting β-catenin.

Oncol Lett 2020 Jan 14;19(1):415-423. Epub 2019 Nov 14.

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.

The oncogenic protein β-catenin is regulated by microRNAs (miRs) in non-small cell lung cancer (NSCLC). miR-512-5p is downregulated in NSCLC compared with healthy tissues and exhibits a tumour-suppressive effect. To study whether miR-512-5p acts on β-catenin to exert its anticancer effect in NSCLC, miR-512-5p mimic and inhibitor were transfected into NSCLC A549 and H1975 cells. miR-512-5p mimic inhibited the invasion of NSCLC cells and increased apoptosis, which suggested an inhibitory effect of miR-512-5p in NSCLC progression . By contrast, transfection with the miR-512-5p inhibitor resulted in the opposite effects. A dual-luciferase assay demonstrated that miR-512-5p complementarily bound to the 3'-untranslated region of β-catenin. miR-512-5p mimic suppressed the transcription and translation of β-catenin and reduced the expression of the downstream oncogenes cyclin D1 and matrix metalloproteinases, leading to the inhibition of Wnt/β-catenin signalling and subsequent inhibition of NSCLC tumourigenesis . In conclusion, miR-512-5p may function as a tumour suppressor in NSCLC by inhibiting the Wnt/β-catenin pathway.
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http://dx.doi.org/10.3892/ol.2019.11102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923952PMC
January 2020

RNPS1 inhibition aggravates ischemic brain injury and promotes neuronal death.

Biochem Biophys Res Commun 2020 02 9;523(1):39-45. Epub 2019 Dec 9.

Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China. Electronic address:

RNA-binding protein with serine-rich domain 1 (RNPS1) is essential for modulating mRNA metabolism, but its role in ischemic stroke is unknown. In this study, we found that RNPS1 expression was significantly up-regulated in the brains of ischemic stroke mice and primary cortical neurons after oxygen-glucose deprivation (OGD) treatment. Knockdown of RNPS1 significantly aggravated ischemic brain injury after middle cerebral artery occlusion (MCAO) and promoted neuronal death. In addition, knockdown of RNPS1 exacerbated ischemia induced neuronal apoptosis, and downregulated the expression of anti-apoptotic proteins Bcl-xL and Mcl-1. Our study suggested that RNPS1 might be a potential therapeutic target for alleviating neuronal death in ischemic stroke.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.185DOI Listing
February 2020

Sensitivity of Reality Monitoring to Fluency: Evidence from Behavioral Performance and Event-Related Potential (ERP) Old/New Effects.

Med Sci Monit 2019 Dec 12;25:9490-9498. Epub 2019 Dec 12.

Department of Anesthesiology, First Hospital, Zhejiang University, Hangzhou, Zhejiang, China (mainland).

BACKGROUND Item memory and source memory are differently processed with both behavioral and event-related potential (ERP) evidence. Reality monitoring, a specific type of source memory, which refers to the ability to differentiate external sources from internal sources, has been drawing much attention. Among factors that have an impact on reality monitoring, fluency has not been well-studied. Therefore, the current study aimed to investigate whether fluency could affect reality monitoring, through observations on both behavioral performance and electrophysiological patterns. MATERIAL AND METHODS Adopting ERP techniques, participants were required either to watch the presentation of a name/picture pair, or to imagine a picture for each displayed name, once (low fluency) or twice (high fluency). Later they completed a reality monitoring task of identifying names as perceived, imagined, or novel items. Behavioral performance was measured, and ERP waveforms were recorded. RESULTS Behaviorally, high fluency items were faster and more accurately attributed to the sources than low fluency items. ERP waveforms revealed that late positive component (LPC) occurred for all 4 types of items, while imagined items of low fluency did not record a robust FN400 or late frontal old/new effect. CONCLUSIONS As results revealed, the factor of fluency does influence reality monitoring in terms of accuracy and responding speed. Meanwhile, for imagined items of low fluency, the absence of FN400 and frontal old/new effect also suggests the sensitivity of reality monitoring to fluency, because these representatives of familiarity-based processing and post-retrieval monitoring are inevitably involved in the process of differentiating internal source from external source.
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http://dx.doi.org/10.12659/MSM.917401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927240PMC
December 2019

STS-NLSP: A Network-Based Label Space Partition Method for Predicting the Specificity of Membrane Transporter Substrates Using a Hybrid Feature of Structural and Semantic Similarity.

Front Bioeng Biotechnol 2019 6;7:306. Epub 2019 Nov 6.

State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.

Membrane transport proteins play crucial roles in the pharmacokinetics of substrate drugs, the drug resistance in cancer and are vital to the process of drug discovery, development and anti-cancer therapeutics. However, experimental methods to profile a substrate drug against a panel of transporters to determine its specificity are labor intensive and time consuming. In this article, we aim to develop an multi-label classification approach to predict whether a substrate can specifically recognize one of the 13 categories of drug transporters ranging from ATP-binding cassette to solute carrier families using both structural fingerprints and chemical ontologies information of substrates. The data-driven network-based label space partition (NLSP) method was utilized to construct the model based on a hybrid of similarity-based feature by the integration of 2D fingerprint and semantic similarity. This method builds predictors for each label cluster (possibly intersecting) detected by community detection algorithms and takes union of label sets for a compound as final prediction. NLSP lies into the ensembles of multi-label classifier category in multi-label learning field. We utilized Cramér's V statistics to quantify the label correlations and depicted them via a heatmap. The jackknife tests and iterative stratification based cross-validation method were adopted on a benchmark dataset to evaluate the prediction performance of the proposed models both in multi-label and label-wise manner. Compared with other powerful multi-label methods, ML-NN, MTSVM, and RAEL, our multi-label classification model of NLPS-RF (random forest-based NLSP) has proven to be a feasible and effective model, and performed satisfactorily in the predictive task of transporter-substrate specificity. The idea behind NLSP method is intriguing and the power of NLSP remains to be explored for the multi-label learning problems in bioinformatics. The benchmark dataset, intermediate results and python code which can fully reproduce our experiments and results are available at https://github.com/dqwei-lab/STS.
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http://dx.doi.org/10.3389/fbioe.2019.00306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851049PMC
November 2019