Publications by authors named "Zichen Wang"

102 Publications

An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions.

Front Cell Dev Biol 2021 19;9:630067. Epub 2021 Mar 19.

Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Cell fate decisions during development are governed by multi-factorial regulatory mechanisms including chromatin remodeling, DNA methylation, binding of transcription factors to specific loci, RNA transcription and protein synthesis. However, the mechanisms by which such regulatory "dimensions" coordinate cell fate decisions are currently poorly understood. Here we quantified the multi-dimensional molecular changes that occur in mouse embryonic stem cells (mESCs) upon depletion of Estrogen related receptor beta (Esrrb), a key pluripotency regulator. Comparative analyses of expression changes subsequent to depletion of Esrrb or Nanog, indicated that a system of interlocked feed-forward loops involving both factors, plays a central part in regulating the timing of mESC fate decisions. Taken together, our meta-analyses support a hierarchical model in which pluripotency is maintained by an Oct4-Sox2 regulatory module, while the timing of differentiation is regulated by a Nanog-Esrrb module.
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http://dx.doi.org/10.3389/fcell.2021.630067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017264PMC
March 2021

Impact of corticosteroids in hospitalised COVID-19 patients.

BMJ Open Respir Res 2021 04;8(1)

Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Corticosteroids are a potential therapeutic agent for patients with COVID-19 pneumonia. The RECOVERY (Randomised Trials in COVID-19 Therapy) trial provided data on the mortality benefits of corticosteroids. The study aimed to determine the association between corticosteroid use on mortality and infection rates and to define subgroups who may benefit from corticosteroids in a real-world setting.

Methods: Clinical data were extracted that included demographic, laboratory data and details of the therapy, including the administration of corticosteroids, azithromycin, hydroxychloroquine, tocilizumab and anticoagulation. The primary outcome was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) admission and invasive mechanical ventilation. Outcomes were compared in patients who did and did not receive corticosteroids using the multivariate Cox regression model.

Results: 4313 patients were hospitalised with COVID-19 during the study period, of whom 1270 died (29.4%). When administered within the first 7 days after admission, corticosteroids were associated with reduced mortality (OR 0.73, 95% CI 0.55 to 0.97, p=0.03) and decreased transfers to the ICU (OR 0.72, 95% CI 0.47 to 1.11, p=0.02). This mortality benefit was particularly impressive in younger patients (<65 years of age), females and those with elevated inflammatory markers, defined as C reactive protein ≥150 mg/L (p≤0.05), interleukin-6 ≥20 pg/mL (p≤0.05) or D-dimer ≥2.0 µg/L (p≤0.05). Therapy was safe with similar rates of bacteraemia and fungaemia in corticosteroid-treated and non-corticosteroid-treated patients.

Conclusion: In patients hospitalised with COVID-19 pneumonia, corticosteroid use within the first 7 days of admission decreased mortality and ICU admissions with no associated increase in bacteraemia or fungaemia.
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http://dx.doi.org/10.1136/bmjresp-2020-000766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023732PMC
April 2021

Experiential marketing: Will it affect customer citizenship behavior? An empirical study of multiple mediation model in Thailand.

Authors:
Zichen Wang

J Community Psychol 2021 Mar 22. Epub 2021 Mar 22.

College of Innovation Management, Suan Sunandha Rajabhat University, Bangkok, Thailand.

The purpose of this study is to examine the consumer's experience of sense, feel, thinking, action, and relate experience in the shopping process whether the consumer is willing to voluntarily make beneficial behaviors for the enterprise. The study also aimed to assess the mediating effect of subjective well-being, brand identity, and received service fairness in the relationship between experimental marketing and customer citizenship behavior. Convenient sampling techniques were used to select samples. After deleting invalid questionnaires, a total of 109 valid questionnaires were recovered for data analysis. The analysis results after using SmartPLS for the structural model show that experience marketing will have a significant positive effect on customer citizenship behavior. The findings of this study extend the company's understanding of the relationship between consumer shopping experience in online shopping platforms, consumer subject well-being, brand identity, perceived service fairness, and customer citizenship behavior. At the same time, this study also provides discussion and enlightenment for the companies that operate online shopping supermarkets, limitations, and suggestions for future research.
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http://dx.doi.org/10.1002/jcop.22550DOI Listing
March 2021

Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring.

Front Neurosci 2021 9;15:634781. Epub 2021 Feb 9.

Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen Mental Health Center, Shenzhen, China.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impaired skills in social interaction and communication in addition to restricted and repetitive behaviors. Many different factors may contribute to ASD development; in particular, oxytocin receptor (OXTR) deficiency has been reported to be associated with ASD, although the detailed mechanism has remained largely unknown. Epidemiological study has shown that maternal diabetes is associated with ASD development. In this study, we aim to investigate the potential role of OXTR on maternal diabetes-mediated social deficits in offspring. Our study of human neuron progenitor cells showed that hyperglycemia induces OXTR suppression and that this suppression remains during subsequent normoglycemia. Further investigation showed that OXTR suppression is due to hyperglycemia-induced persistent oxidative stress and epigenetic methylation in addition to the subsequent dissociation of estrogen receptor β (ERβ) from the OXTR promoter. Furthermore, our mouse study showed that maternal diabetes induces OXTR suppression; prenatal OXTR deficiency mimics and potentiates maternal diabetes-mediated anxiety-like behaviors, while there is less of an effect on autism-like behaviors. Additionally, postnatal infusion of OXTR partly, while infusion of ERβ completely, reverses maternal diabetes-induced social deficits. We conclude that OXTR may be an important factor for ASD development and that maternal diabetes-induced suppression of oxytocin receptor contributes to social deficits in offspring.
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http://dx.doi.org/10.3389/fnins.2021.634781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900564PMC
February 2021

Three-dimensional ordered magnetic macroporous metal-organic frameworks for enzyme immobilization.

J Colloid Interface Sci 2021 May 2;590:436-445. Epub 2021 Feb 2.

State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China; Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address:

Metal-organic frameworks (MOFs) have been emerged as a promising support for immobilizing enzymes owing to the tunable porosity, high surface area, and structural diversity. However, most of these possess nanometer size and small pores, which are difficult to recover them from the reaction medium and present low immobilization efficiency and protein loading capacity, and high substrate diffusion limitations. Herein, a novel magnetic amino-functionalized zeolitic imidazolate framework-8 (ZIF-8) with 3D highly ordered macroporous structure was synthesized using the assembled polystyrene (PS) nanosphere monoliths as a template. Subsequently, catalase (CAT) molecules were immobilized on the surface of macroporous magnetic ZIF-8 and inside the macropores by precipitation, covalent binding and cross-linking. The resultant immobilized CAT showed high immobilization efficiency (58%) and protein loading capacity (29%), leading to 500% higher activity than the immobilized CAT on ZIF-8 (CAT/ZIF-8). Meanwhile, the immobilized CAT could be easily recovered with a magnet without obvious activity loss. The traditional CAT/ZIF-8 lost its activity after 6 cycles, whereas, the immobilized CAT retained 90% activity of its initial activity after reusing for 8 cycles, indicating excellent reusability. In conclusion, this study provides a facile and efficient approach to immobilize enzymes on/in MOFs with enhanced activity and excellent recyclability.
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http://dx.doi.org/10.1016/j.jcis.2021.01.078DOI Listing
May 2021

Novel Mesoporous Lignin-Calcium for Efficiently Scavenging Cationic Dyes from Dyestuff Effluent.

ACS Omega 2021 Jan 29;6(1):816-826. Epub 2020 Dec 29.

College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 210009, China.

A novel adsorbent lignin-calcium was fabricated by a simple flocculation-sedimentation approach to remove methylene blue. The structure and morphology of the well-prepared sample were analyzed by multiple characterization methods. Lignin-calcium microspheres demonstrated a mesoporous and inserted layer structure with a coarse surface. Methylene blue (MB) adsorption by lignin-calcium complied with the Langmuir model, showing a maximum adsorption amount of 803.9 mg/g, exceeding that reported in the literature by 3-22-fold. The adsorption kinetics matched the pseudo-second-order model well. The pore volume diffusion model was technically applied to evaluate the mass transfer mechanisms. The effective pore volume diffusion coefficient was 6.28 × 10 m/s. Furthermore, lignin-calcium exhibited excellent adsorbability for methylene blue across a pH range from 3 to 11 and could be regenerated by hydrochloric acid with an elution efficiency of 62.44%. Multiple mechanisms may support the adsorption. Altogether, the tailor-made lignin-calcium is promising as an efficient and sustainable adsorbent for scavenging cationic dyes from dyestuff effluent.
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http://dx.doi.org/10.1021/acsomega.0c05401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808136PMC
January 2021

Vitamin D deficiency worsens maternal diabetes induced neurodevelopmental disorder by potentiating hyperglycemia-mediated epigenetic changes.

Ann N Y Acad Sci 2021 05 10;1491(1):74-88. Epub 2020 Dec 10.

Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen, P.R. China.

Many studies have shown that vitamin D (VD) deficiency may be a risk factor for neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, although causative mechanisms remain unknown. In this study, we investigated the potential role and effect of VD on maternal diabetes induced autism-related phenotypes. The in vitro study found that enhancing genomic VD signaling by overexpressing the VD receptor (VDR) in human neural progenitor cells ACS-5003 protects against hyperglycemia-induced oxidative stress and inflammation by activating Nrf2 and its target genes, including SOD2 and HMOX1, and accordingly, VDR gene knockdown worsens the problem. In the two in vivo models we explored, maternal diabetes was used to establish an animal model of relevance to ASD, and mice lacking 25-hydroxyvitamin D 1-alpha-hydroxylase (the rate-limiting enzyme in the synthesis of 1,25(OH)2D3) were used to develop a model of VD deficiency (VDD). We show that although prenatal VDD itself does not produce ASD-relevant phenotypes, it significantly potentiates maternal diabetes induced epigenetic modifications and autism-related phenotypes. Postnatal manipulation of VD has no effect on maternal diabetes induced autism-related phenotypes. We conclude that VDD potentiates maternal diabetes induced autism-related phenotypes in offspring by epigenetic mechanisms. This study adds to other preclinical studies linking prenatal VDD with a neurodevelopmental disorder.
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http://dx.doi.org/10.1111/nyas.14535DOI Listing
May 2021

Combination of and Ameliorates Vascular Endothelial Cell Dysfunction by Inhibiting Oxidative Stress.

Evid Based Complement Alternat Med 2020 18;2020:6031782. Epub 2020 Sep 18.

Department of Editorial, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.

Vascular endothelial dysfunction is an essential and early sign of diabetic macroangiopathy, a primary complication of diabetes mellitus. - is a classic medical combination applied in China to treat diabetes mellitus. The aim of this study was to investigate the effect of the granule form of the extract produced from the dried root of (AM) combination with the granule form of the extract produced from the dried (AS) on diabetic macroangiopathy and its underlying mechanism. Herein, rats were treated by AM-AS at a ratio of 3 : 2 via intragastric administration. High glucose-induced human umbilical vein vascular endothelial cells (HUVECs) were then treated with drug-containing serum collected from the rats. In high glucose-treated HUVECs, AM-AS combination increased cell viability ( < 0.05), decreased the percentage of apoptotic cells ( < 0.05) and the expression of the proapoptosis protein caspase 3 ( < 0.05), reduced the proportion of cells in the G0/G1 phase ( < 0.05), decreased reactive oxygen species level ( < 0.05), enhanced cell migration and invasion ( < 0.05), and reduced the level of 8-iso-prostaglandin F2alpha. These results indicate that AM-AS combination at the ratio of 3 : 2 ameliorated HUVEC dysfunction by regulating apoptosis, cell migration, and invasion, which might be mediated by their regulatory effect on reactive oxygen species production. The current study provides a theoretical basis for the treatment of diabetic macroangiopathy using AM-AS.
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http://dx.doi.org/10.1155/2020/6031782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714576PMC
September 2020

Sex differences in viral entry protein expression, host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment in COVID-19.

Res Sq 2020 Nov 4. Epub 2020 Nov 4.

Epidemiological studies suggest that men exhibit a higher mortality rate to COVID-19 than women, yet the underlying biology is largely unknown. Here, we seek to delineate sex differences in the expression of entry genes and , host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment. Using over 220,000 human gene expression profiles covering a wide range of age, tissues, and diseases, we found that male samples show higher expression levels of and , especially in the older group (>60 years) and in the kidney. Analysis of 6,031 COVID-19 patients at Mount Sinai Health System revealed that men have significantly higher creatinine levels, an indicator of impaired kidney function. Further analysis of 782 COVID-19 patient gene expression profiles taken from upper airway and blood suggested men and women present profound expression differences in responses to SARS-CoV-2. Computational deconvolution analysis of these profiles revealed male COVID-19 patients have enriched kidney-specific mesangial cells in blood compared to healthy patients. Finally, we observed selective estrogen receptor modulators, but not other hormone drugs (agonists/antagonists of estrogen, androgen, and progesterone), could reduce SARS-CoV-2 infection in vitro.
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http://dx.doi.org/10.21203/rs.3.rs-100914/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654875PMC
November 2020

Paper-based biosensor based on phenylalnine ammonia lyase hybrid nanoflowers for urinary phenylalanine measurement.

Int J Biol Macromol 2021 Jan 30;166:601-610. Epub 2020 Oct 30.

State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin University of Science and Technology, No 29, 13th, Avenue, Tianjin Economic and Technological Development Area (TEDA), Tianjin 300457, PR China. Electronic address:

The Phenylketonuria (PKU) is an inborn defect of phenylalanine (Phe) metabolism, in which Phe accumulated in the blood causing alterations at the central nervous system. Therefore, the detection of PKU is very important for the early diagnosis of PKU patients. However, existing tests for PKU are time-consuming and require high-resource laboratories. In this study, a novel paper-based biosensor based on phenylalnine ammonia lyase (PAL) hybrid nanoflowers was constructed that provides a semi-quantitative output of the concentration of Phe from urine samples. PAL@Ca(PO) hybrid nanoflowers (PAL@NF) were first prepared using PAL and Ca. Synthesis conditions of the PAL@NF on the formation of the PAL@NF were optimized. The PAL@NF exhibited 90% activity recovery under optimal condition. Compared with free PAL, the PAL@NF displayed good storage stability and increased tolerance to proteolysis. After five consecutive operating cycles, the PAL@NF still retained 73% of its initial activity, indicating excellent reusability. Furthermore, the paper-based biosensor was able to detect Phe concentration in urine samples, and exhibited good linearity to the Phe concentrations in the range from 60 to 2400 μM and the response time was only about 10 min. Therefore, the paper-based biosensor can be a promising candidate as a biosensor for the detection of PKU.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.10.218DOI Listing
January 2021

Hospitalised COVID-19 patients of the Mount Sinai Health System: a retrospective observational study using the electronic medical records.

BMJ Open 2020 10 26;10(10):e040441. Epub 2020 Oct 26.

Sema4, Stamford, Connecticut, USA

Objective: To assess association of clinical features on COVID-19 patient outcomes.

Design: Retrospective observational study using electronic medical record data.

Setting: Five member hospitals from the Mount Sinai Health System in New York City (NYC).

Participants: 28 336 patients tested for SARS-CoV-2 from 24 February 2020 to 15 April 2020, including 6158 laboratory-confirmed COVID-19 cases.

Main Outcomes And Measures: Positive test rates and in-hospital mortality were assessed for different racial groups. Among positive cases admitted to the hospital (N=3273), we estimated HR for both discharge and death across various explanatory variables, including patient demographics, hospital site and unit, smoking status, vital signs, lab results and comorbidities.

Results: Hispanics (29%) and African Americans (25%) had disproportionately high positive case rates relative to their representation in the overall NYC population (p<0.05); however, no differences in mortality rates were observed in hospitalised patients based on race. Outcomes differed significantly between hospitals (Gray's T=248.9; p<0.05), reflecting differences in average baseline age and underlying comorbidities. Significant risk factors for mortality included age (HR 1.05, 95% CI 1.04 to 1.06; p=1.15e-32), oxygen saturation (HR 0.985, 95% CI 0.982 to 0.988; p=1.57e-17), care in intensive care unit areas (HR 1.58, 95% CI 1.29 to 1.92; p=7.81e-6) and elevated creatinine (HR 1.75, 95% CI 1.47 to 2.10; p=7.48e-10), white cell count (HR 1.02, 95% CI 1.01 to 1.04; p=8.4e-3) and body mass index (BMI) (HR 1.02, 95% CI 1.00 to 1.03; p=1.09e-2). Deceased patients were more likely to have elevated markers of inflammation.

Conclusions: While race was associated with higher risk of infection, we did not find racial disparities in inpatient mortality suggesting that outcomes in a single tertiary care health system are comparable across races. In addition, we identified key clinical features associated with reduced mortality and discharge. These findings could help to identify which COVID-19 patients are at greatest risk of a severe infection response and predict survival.
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http://dx.doi.org/10.1136/bmjopen-2020-040441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592304PMC
October 2020

Maternal Diabetes Induces Immune Dysfunction in Autistic Offspring Through Oxidative Stress in Hematopoietic Stem Cells.

Front Psychiatry 2020 3;11:576367. Epub 2020 Sep 3.

Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen, China.

Autism spectrum disorders (ASD) have been found to be associated with immune dysfunction and elevated cytokines, although the detailed mechanism remains unknown. In this study, we aim to investigate the potential mechanisms through a maternal diabetes-induced autistic mouse model. We found that maternal diabetes-induced autistic offspring have epigenetic changes on the superoxide dismutase 2 (SOD2) promoter with subsequent SOD2 suppression in both hematopoietic stem cells (HSC) and peripheral blood mononuclear cells (PBMC). Bone marrow transplantation of normal HSC to maternal diabetes-induced autistic offspring transferred epigenetic modifications to PBMC and significantly reversed SOD2 suppression and oxidative stress and elevated inflammatory cytokine levels. Further, human study showed that SOD2 mRNA expression from PBMC in the ASD group was reduced to ~12% compared to typically developing group, and the SOD2 mRNA level-based ROC (Receiver Operating Characteristic) curve shows a very high sensitivity and specificity for ASD patients. We conclude that maternal diabetes induces immune dysfunction in autistic offspring through SOD2 suppression and oxidative stress in HSC. SOD2 mRNA expression in PBMC may be a good biomarker for ASD diagnosis.
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http://dx.doi.org/10.3389/fpsyt.2020.576367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495463PMC
September 2020

Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease.

Diabetes 2021 02 16;70(2):589-602. Epub 2020 Oct 16.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

Diabetic kidney disease (DKD) remains the most common cause of kidney failure, and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD-related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 data set, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor was of members of the TNF-α/NF-κB, JAK/STAT, and TGF-β/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-κB and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.
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http://dx.doi.org/10.2337/db20-0580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881868PMC
February 2021

Anisotropic Seeded Growth of Ag Nanoplates Confined in Shape-Deformable Spaces.

Angew Chem Int Ed Engl 2021 Feb 28;60(8):4117-4124. Epub 2021 Jan 28.

Department of Chemistry, University of California, Riverside, CA, 92521, USA.

Conventional templating synthesis confines the growth of seeds in rigid spaces to achieve faithful morphological replication. Herein, we explore the use of spherical shape-deformable polymeric nanoshells to regulate the anisotropic growth of Ag nanoplates. The flexible shells deform adaptively to accommodate the initial overgrowth of the seeds but restrict the growth in the directions where the shells are fully stretched, eventually producing nanoplates with an unconventional circular profile. The diameter of the final Ag nanoplates can be precisely predicted by stretching and flattering the nanoshells into a plate-like capsule while retaining their original internal surface area. Furthermore, unlike conventional templates, the polymer shells eventually turn themselves into a conformal coating that binds to the surface of the full-grown Ag nanoplates and significantly enhances their stability against oxidative etching.
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http://dx.doi.org/10.1002/anie.202011334DOI Listing
February 2021

Miniature Fluorescence Microscopy for Imaging Brain Activity in Freely-Behaving Animals.

Neurosci Bull 2020 Oct 14;36(10):1182-1190. Epub 2020 Aug 14.

State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, PKU-Nanjing Institute of Translational Medicine, Peking University, Beijing, 100871, China.

An ultimate goal of neuroscience is to decipher the principles underlying neuronal information processing at the molecular, cellular, circuit, and system levels. The advent of miniature fluorescence microscopy has furthered the quest by visualizing brain activities and structural dynamics in animals engaged in self-determined behaviors. In this brief review, we summarize recent advances in miniature fluorescence microscopy for neuroscience, focusing mostly on two mainstream solutions - miniature single-photon microscopy, and miniature two-photon microscopy. We discuss their technical advantages and limitations as well as unmet challenges for future improvement. Examples of preliminary applications are also presented to reflect on a new trend of brain imaging in experimental paradigms involving body movements, long and complex protocols, and even disease progression and aging.
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http://dx.doi.org/10.1007/s12264-020-00561-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532237PMC
October 2020

Toward heterogeneous information fusion: bipartite graph convolutional networks for in silico drug repurposing.

Bioinformatics 2020 07;36(Suppl_1):i525-i533

Computational Diagnostics Lab, Departments of Radiology and Pathology, Los Angeles, CA 90095, USA.

Motivation: Mining drug-disease association and related interactions are essential for developing in silico drug repurposing (DR) methods and understanding underlying biological mechanisms. Recently, large-scale biological databases are increasingly available for pharmaceutical research, allowing for deep characterization for molecular informatics and drug discovery. However, DR is challenging due to the molecular heterogeneity of disease and diverse drug-disease associations. Importantly, the complexity of molecular target interactions, such as protein-protein interaction (PPI), remains to be elucidated. DR thus requires deep exploration of a multimodal biological network in an integrative context.

Results: In this study, we propose BiFusion, a bipartite graph convolution network model for DR through heterogeneous information fusion. Our approach combines insights of multiscale pharmaceutical information by constructing a multirelational graph of drug-protein, disease-protein and PPIs. Especially, our model introduces protein nodes as a bridge for message passing among diverse biological domains, which provides insights into utilizing PPI for improved DR assessment. Unlike conventional graph convolution networks always assuming the same node attributes in a global graph, our approach models interdomain information fusion with bipartite graph convolution operation. We offered an exploratory analysis for finding novel drug-disease associations. Extensive experiments showed that our approach achieved improved performance than multiple baselines for DR analysis.

Availability And Implementation: Source code and preprocessed datasets are at: https://github.com/zcwang0702/BiFusion.
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http://dx.doi.org/10.1093/bioinformatics/btaa437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355266PMC
July 2020

Demographic characteristics and neuropsychological assessments of subjective cognitive decline (SCD) (plus).

Ann Clin Transl Neurol 2020 06;7(6):1002-1012

Department of Neurology, XuanWu Hospital of Capital Medical University, Beijing, China.

Background: Since SCD (plus) was standardized, little is known about its demographic characteristics and its outcomes of neuropsychological assessments, including the SCD questionnaire 9 (SCD-Q9).

Objective: To characterize SCD (plus) by comparing the neuropsychological features among its subgroups and with normal controls (NC). Also, to explore its demographics and to understand the relation of the chief complaints and the scores of SCD-Q9.

Methods: Multistage stratified cluster random sampling was conducted to select participants. As a result, 84 NC and 517 SCD (plus) were included. SCD (plus) was further classified into several subgroups (SCD-C: concerned cognitive decline; SCD-F: complaints about SCD within the past five years; SCD-P: feeling performance being not as good as their peers; SCD+: presented> 3 of SCD (plus) features; SCD-: presented ≤ 3 of SCD (plus) features (see the diagnostic criteria for the details)) and between-group comparisons of neuropsychological scores were conducted. Point-biserial correlation and binary logistic regression analyses were performed to investigate the demographic characteristics of its subgroups. Finally, Spearman correlation was used to better understand the relation of SCD (plus) to SCD-Q9.

Results: (1) Scores of AVLT-LR (AVLT-LR: Auditory Verbal Learning Test-Long Delayed Recall) and MoCA-B (MoCA: Montreal Cognitive Assessment-Basic) were lower in the SCD-P group than those in the NC group, and the SCD+ group scored lower in the MoCA-B and CDT(CDT: Clock Drawing Test) than the SCD- group. (2) Females were more concerned than male participants. Individuals with lower education level felt that their cognitive performance were worse than their peers. Also, younger people might express concerns more than the more elderly. People who had complaints of SCD-P might be more likely to report SCD-C, but less likely to report SCD-F. (3) Positive correlations were found between the chief complaints of SCD (plus) and some items of SCD-Q9.

Conclusions: SCD (plus) may be related to demographic factors. Individuals with SCD (plus) already exhibited cognitive impairment, which can be detected by SCD-Q9.
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http://dx.doi.org/10.1002/acn3.51068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317645PMC
June 2020

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

JACC Basic Transl Sci 2020 Apr 8;5(4):376-386. Epub 2020 Apr 8.

Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins , , and and the regulators of small GTPase signaling and are critical to cardiac development.
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http://dx.doi.org/10.1016/j.jacbts.2020.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188873PMC
April 2020

Berberine Ameliorates Prenatal Dihydrotestosterone Exposure-Induced Autism-Like Behavior by Suppression of Androgen Receptor.

Front Cell Neurosci 2020 9;14:87. Epub 2020 Apr 9.

Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen, China.

Many epidemiology studies have shown that maternal polycystic ovary syndrome (PCOS) results in a greater risk of autism spectrum disorders (ASD) development, although the detailed mechanism remains unclear. In this study, we aimed to investigate the potential mechanism and provide a possible treatment for PCOS-mediated ASD through three experiments: Experiment 1: real-time PCR and western blots were employed to measure gene expression in human neurons, and the luciferase reporter assay and chromatin immunoprecipitation (ChIP) was used to map the responsive elements on related gene promoters. Experiment 2: pregnant dams were prenatally exposed to dihydrotestosterone (DHT), androgen receptor (AR) knockdown (shAR) in the amygdala, or berberine (BBR), and the subsequent male offspring were used for autism-like behavior (ALB) assay followed by biomedical analysis, including gene expression, oxidative stress, and mitochondrial function. Experiment 3: the male offspring from prenatal DHT exposed dams were postnatally treated by either shAR or BBR, and the offspring were used for ALB assay followed by biomedical analysis. Our findings showed that DHT treatment suppresses the expression of estrogen receptor β (ERβ) and superoxide dismutase 2 (SOD2) through AR-mediated hypermethylation on the ERβ promoter, and BBR treatment suppresses AR expression through hypermethylation on the AR promoter. Prenatal DHT treatment induces ERβ suppression, oxidative stress and mitochondria dysfunction in the amygdala with subsequent ALB behavior in male offspring, and AR knockdown partly diminishes this effect. Furthermore, both prenatal and postnatal treatment of BBR partly restores prenatal DHT exposure-mediated ALB. In conclusion, DHT suppresses ERβ expression through the AR signaling pathway by hypermethylation on the ERβ promoter, and BBR restores this effect through AR suppression. Prenatal DHT exposure induces ALB in offspring through AR-mediated ERβ suppression, and both prenatal and postnatal treatment of BBR ameliorates this effect. We conclude that BBR ameliorates prenatal DHT exposure-induced ALB through AR suppression, this study may help elucidate the potential mechanism and identify a potential treatment through using BBR for PCOS-mediated ASD.
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http://dx.doi.org/10.3389/fncel.2020.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161090PMC
April 2020

Comprehensive mutanome analysis of Lewis lung cancer reveals immunogenic neoantigens for therapeutic vaccines.

Biochem Biophys Res Commun 2020 05 27;525(3):607-613. Epub 2020 Feb 27.

College of Bio-Medicine and Health, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; Taihe Hospital, Shiyan, Hubei, 442000, China; Hubei Cancer Hospital, Wuhan, Hubei, 430079, China. Electronic address:

Personalized neoantigen vaccines are capable of eliciting vigorous T-cell responses and have been demonstrated to achieve striking therapeutic effects against cancer. Here we performed comprehensive mutanome analysis of the mouse Lewis lung cancer cells to identify tumor neoantigens followed by prediction of their MHC affinity and immunogenicity. We adopted a strategy that enables us to select neoantigens that were predicted to have high affinity to both MHC I and MHC II. Ten neoantigens were selected to synthesize peptide vaccines and tested in vivo for immunogenicity. Four neoantigen peptide vaccines were found to elicit robust immune reactivity and were further examined for tumor inhibition in mice with xenografted LLC tumors. Two neoantigen peptide vaccines showed significant inhibition on tumor growth and prolonged the survival of tumor-bearing mice. Our studies explored the neoantigen peptide vaccines to treat lung cancer and provide rationale for the optimization of tumor neoantigen selection for therapeutic vaccines.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.132DOI Listing
May 2020

Awareness and Attitudes Toward Advance Care Planning Among Community-Dwelling Older Adults in China: A Mixed-Methods Study.

Am J Hosp Palliat Care 2020 Sep 13;37(9):743-749. Epub 2020 Feb 13.

School of Nursing and Health, Zhengzhou University, Zhengzhou, China.

Context: Quality of palliative care and death in mainland China is at a low level of the rest of the world, the public is lacked of proper understanding of the relevant information is one of the important reasons. There has been a shift in policy of palliative care in municipalities recently in mainland China.

Objectives: To measure the advance care planning-related knowledge and attitudes of Chinese community-dwelling older adults, in the hope of presenting a specific implementation of the strategy.

Methods: We conducted a mixed-method sequential explanatory study, composed of a quantitative survey followed by qualitative interviews. The first quantitative phase included 523 community elderly individuals, who completed a validated questionnaire. After statistical analysis, a semistructured qualitative interview has been developed and conducted with 16 of them in order to help explain findings obtained in the first phase.

Results: The study was conducted with 523 community-dwelling older adults. The cognition level of advance care planning (ACP) was low, and attitude toward ACP was active. Living alone or living with a spouse (and children), have a religion, poor health condition, and life-sustaining treatment-related experience can affect how they behave with ACP. However, lack of trust in ACP, lack of life education and relevant legislation or policies, and Chinese traditional culture and emotion may impede their take-up.

Conclusions: This study indicated that the awareness and participation of ACP of community-dwelling older adults in mainland China are not enough. The influence of national conditions and culture should be fully considered during the process of ACP development.
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http://dx.doi.org/10.1177/1049909120905255DOI Listing
September 2020

Influence of Structured Water Layers on Protein Adsorption Process: A Case Study of Cytochrome and Carbon Nanotube Interactions and Its Implications.

J Phys Chem B 2020 01 15;124(4):684-694. Epub 2020 Jan 15.

Center of Materials Science and Optoelectronics Engineering, College of Materials Science and Opto-Electronic Technology , University of Chinese Academy of Sciences , Beijing 100049 , P. R. China.

Cytochrome , an essential protein of the electron transport chain, is known to be capable of amplifying the toxicity of carbon nanomaterials via free-radical generation. To understand their interaction, as well as the more general protein-nanoparticle interaction at molecular levels, we investigate the adsorptions between cytochrome and carbon nanotubes (CNTs) in dynamic and thermodynamic ways using molecular dynamics simulations. The results reveal a well-defined three-phase process separated by two transition points: the diffusion phase where the protein diffuses in the water box, the lockdown phase I where the protein inserts into the surface-bound water layers and rearranges its conformation to fit to the surface of the CNT, and the lockdown phase II where cytochrome repels the water molecules standing in its way to the surface of CNT and reaches stable adsorption states. The structured water layers affect the movement of atoms by electrostatic forces. In lockdown phase I, the conformation adjustment of the protein dominates the adsorption process. The most thermally favorable adsorption conformation is determined. It shows that except for the deformation of short β sheets and some portions of α helixes, most of the secondary structures of cytochrome remain unchanged, implying that most of the functions of cytochrome are preserved. During these processes, the energy contributions of the hydrophilic residues of cytochrome are much larger than those of hydrophobic residues. Interestingly, the structured water layers at the CNT surface allow more hydrophilic residues such as Lys to get into close contact with the CNT, which plays a significant role during the anchoring process of adsorption. Our results demonstrate that the heme group is in close contact with the CNT in some of the adsorbed states, which hence provides a way for electron transfer from cytochrome to the CNT surface.
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http://dx.doi.org/10.1021/acs.jpcb.9b10192DOI Listing
January 2020

Dermal sheath contraction powers stem cell niche relocation during hair cycle regression.

Science 2020 01 19;367(6474):161-166. Epub 2019 Dec 19.

Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Tissue homeostasis requires the balance of growth by cell production and regression through cell loss. In the hair cycle, during follicle regression, the niche traverses the skin through an unknown mechanism to reach the stem cell reservoir and trigger new growth. Here, we identify the dermal sheath that lines the follicle as the key driver of tissue regression and niche relocation through the smooth muscle contractile machinery that generates centripetal constriction force. We reveal that the calcium-calmodulin-myosin light chain kinase pathway controls sheath contraction. When this pathway is blocked, sheath contraction is inhibited, impeding follicle regression and niche relocation. Thus, our study identifies the dermal sheath as smooth muscle that drives follicle regression for reuniting niche and stem cells in order to regenerate tissue structure during homeostasis.
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http://dx.doi.org/10.1126/science.aax9131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409777PMC
January 2020

Coaction of Electrostatic and Hydrophobic Interactions: Dynamic Constraints on Disordered TrkA Juxtamembrane Domain.

J Phys Chem B 2019 12 11;123(50):10709-10717. Epub 2019 Dec 11.

Department of Cancer Biology , University of Cincinnati College of Medicine , Cincinnati , Ohio 45267 , United States.

In the receptor tyrosine kinase family, conformational change induced by ligand binding is transmitted across the membrane via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Membrane dynamics makes it challenging to study the structural mechanism of receptor activation experimentally. In this study, we employ all-atom molecular dynamics with highly mobile membrane mimetic (HMMM) to capture the native conformation of the JMD in tropomyosin receptor kinase A (TrkA). We find that phosphatidylinositol 4,5-bisphosphate (PIP) lipids engage in stable binding with multiple basic residues. Anionic lipids can compete with salt bridges within the peptide and alter TrkA-JMD conformation. We discover three-residue insertion into the membrane and are able to either enhance or reduce the level of insertion through computationally-designed point mutations. The vesicle-binding experiment supports computational results and indicates that hydrophobic insertion is comparable to electrostatic binding for membrane anchoring. Biochemical assays on cell lines with mutated TrkA show that enhanced TrkA-JMD insertion promotes receptor degradation but does not affect the short-term signaling capacity. Our joint work points to a scenario where lipid headgroups and tails interact with basic and hydrophobic residues on disordered domain, respectively, to restrain flexibility and potentially modulate protein function.
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http://dx.doi.org/10.1021/acs.jpcb.9b09352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162675PMC
December 2019

Maternal diabetes induces autism-like behavior by hyperglycemia-mediated persistent oxidative stress and suppression of superoxide dismutase 2.

Proc Natl Acad Sci U S A 2019 11 4;116(47):23743-23752. Epub 2019 Nov 4.

Joint Center of Translational Precision Medicine, Guangzhou Institute of Pediatrics, Guangzhou Women and Children Medical Center, 510623 Guangzhou, China;

Epidemiological studies show that maternal diabetes is associated with an increased risk of autism spectrum disorders (ASDs), although the detailed mechanisms remain unclear. The present study aims to investigate the potential effect of maternal diabetes on autism-like behavior in offspring. The results of in vitro study showed that transient hyperglycemia induces persistent reactive oxygen species (ROS) generation with suppressed superoxide dismutase 2 (SOD2) expression. Additionally, we found that SOD2 suppression is due to oxidative stress-mediated histone methylation and the subsequent dissociation of early growth response 1 (Egr1) on the SOD2 promoter. Furthermore, in vivo rat experiments showed that maternal diabetes induces SOD2 suppression in the amygdala, resulting in autism-like behavior in offspring. SOD2 overexpression restores, while SOD2 knockdown mimics, this effect, indicating that oxidative stress and SOD2 expression play important roles in maternal diabetes-induced autism-like behavior in offspring, while prenatal and postnatal treatment using antioxidants permeable to the blood-brain barrier partly ameliorated this effect. We conclude that maternal diabetes induces autism-like behavior through hyperglycemia-mediated persistent oxidative stress and SOD2 suppression. Here we report a potential mechanism for maternal diabetes-induced ASD.
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http://dx.doi.org/10.1073/pnas.1912625116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876200PMC
November 2019

The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways.

Sci Data 2019 10 31;6(1):252. Epub 2019 Oct 31.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, 77030, USA.

Mining of integrated public transcriptomic and ChIP-Seq (cistromic) datasets can illuminate functions of mammalian cellular signaling pathways not yet explored in the research literature. Here, we designed a web knowledgebase, the Signaling Pathways Project (SPP), which incorporates community classifications of signaling pathway nodes (receptors, enzymes, transcription factors and co-nodes) and their cognate bioactive small molecules. We then mapped over 10,000 public transcriptomic or cistromic experiments to their pathway node or biosample of study. To enable prediction of pathway node-gene target transcriptional regulatory relationships through SPP, we generated consensus 'omics signatures, or consensomes, which ranked genes based on measures of their significant differential expression or promoter occupancy across transcriptomic or cistromic experiments mapped to a specific node family. Consensomes were validated using alignment with canonical literature knowledge, gene target-level integration of transcriptomic and cistromic data points, and in bench experiments confirming previously uncharacterized node-gene target regulatory relationships. To expose the SPP knowledgebase to researchers, a web browser interface was designed that accommodates numerous routine data mining strategies. SPP is freely accessible at https://www.signalingpathways.org .
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http://dx.doi.org/10.1038/s41597-019-0193-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823428PMC
October 2019

PM promotes replication of VSV by ubiquitination degradation of phospho-IRF3 in A549 cells.

Toxicol In Vitro 2020 Feb 24;62:104698. Epub 2019 Oct 24.

Department of Pathogen Biology, School of Medicine, Jinan University, Guangzhou 510632, China; Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, Guangdong 510632, China; Guangdong Key Laboratory of Virology, the Key Laboratory for Virology of Guangzhou, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. Electronic address:

Both PM and respiratory viruses are part of the atmospheric constituents. Respiratory viruses are often associated with PM exposure, but the mechanism of toxicity remains to be explored. The vitro models that adequately reproduce healthy cells or diseased cells exposing to PM and infecting VSV can provide a useful tool for studying innate immune mechanisms and investigating new therapeutic focus. In the environment of PM, an infection model in which VSV infected A549 cells was established, that mimics the state in which the antiviral innate immune pathways are activated after the respiratory system is infected with RNA viruses. Subsequently, the model was exposed to PM for 24 h. PM could be ingested by A549 cells and synergize with VSV to inhibit cell viability and promote apoptosis. The expression of VSV-G were more abundant after VSV-infected A549 cells were exposed to PM. Furthermore, PM inhibits VSV-induced IFN-β expression in A549 cells. ISG15, CCL-5, and CXCL-10 had the same expression tendency with IFN-β mRNA, consistently. Interestingly, when MG132 was applied, the expression of p-IRF-3 and IFN-β proteins reduced by PM were refreshed. Conversely, the expression of VSV-G proteins were decreased. PM could degrade p-IRF-3 proteins by ubiquitination pathway to inhibit VSV-induced IFN-β expression in A549 cells. Therefore, replication of the VSV viruses was promoted.
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http://dx.doi.org/10.1016/j.tiv.2019.104698DOI Listing
February 2020

Habenular TCF7L2 links nicotine addiction to diabetes.

Nature 2019 10 16;574(7778):372-377. Epub 2019 Oct 16.

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.
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http://dx.doi.org/10.1038/s41586-019-1653-xDOI Listing
October 2019

Biomass-based Hierarchical Porous Carbon for Supercapacitors: Effect of Aqueous and Organic Electrolytes on the Electrochemical Performance.

ChemSusChem 2019 Dec 28;12(23):5099-5110. Epub 2019 Oct 28.

State Key Laboratory of Chemical Resource Engineering, College of Chemical Engineering, Beijing University of Chemical Technology, Beijing, 100029, P.R. China.

Biomass-based hierarchical porous carbon (SCPC) exhibits excellent electrochemical performance in electric double layer capacitors, prepared by carbonization and activation of straw cellulose. To investigate the potential applications of SCPC in supercapacitors, the effect of aqueous and organic electrolytes on the electrochemical performance of SCPC was studied in detail. In H SO , the SCPC electrode exhibits higher specific capacitance (358 F g ) and outstanding cycling stability with 95.6 % capacitance retention over 10 000 cycles. The SCPC electrode shows superior rate capability with 90.7 % capacitance retention in KOH, and higher energy density of 17.9 Wh kg in Na SO . The SCPC electrode exhibits ideal capacitance characteristics, superior rate capability with capacitance retention of 95.8 %, and high energy density of 36.0 Wh kg in tetraethylammonium tetrafluoroborate/propylene carbonate (Et NBF /PC). The significant difference of capacitive performance of SCPC electrode in various electrolytes is mainly attributed to the difference in the electrolyte ion size, ionic conductivity, matching between the electrolyte ions and pore structure, and matching between anions and cations adsorbed on the positive and negative electrodes. This work not only establishes the relationship between the structure of SCPC and its electrochemical performance in different electrolytes, but also provides a reference for the high value-added utilization of SCPC.
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http://dx.doi.org/10.1002/cssc.201902218DOI Listing
December 2019

Single-cell immune landscape of human atherosclerotic plaques.

Nat Med 2019 10 7;25(10):1576-1588. Epub 2019 Oct 7.

Cardiovascular Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke). Plaques from symptomatic patients were characterized by a distinct subset of CD4 T cells and by T cells that were activated and differentiated. Moreover, some T cell subsets in these plaques presented markers of T cell exhaustion. Additionally, macrophages from these plaques contained alternatively activated phenotypes, including subsets associated with plaque vulnerability. In plaques from asymptomatic patients, T cells and macrophages were activated and displayed evidence of interleukin-1β signaling. The identification of specific features of innate and adaptive immune cells in plaques that are associated with cerebrovascular events may enable the design of more precisely tailored cardiovascular immunotherapies.
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http://dx.doi.org/10.1038/s41591-019-0590-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318784PMC
October 2019