Publications by authors named "Yang Shi"

885 Publications

Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms.

Neuron 2021 Jun 10. Epub 2021 Jun 10.

Department of Neurology, Washington University, St. Louis, MO 63110, USA. Electronic address:

APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.
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http://dx.doi.org/10.1016/j.neuron.2021.05.034DOI Listing
June 2021

Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia.

iScience 2021 Jun 25;24(6):102651. Epub 2021 May 25.

Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.

A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML.
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http://dx.doi.org/10.1016/j.isci.2021.102651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192696PMC
June 2021

Thermal treatment's enhancement on high solid anaerobic digestion: effects of temperature and reaction time.

Environ Sci Pollut Res Int 2021 Jun 18. Epub 2021 Jun 18.

School of Civil and Surveying & Mapping Engineering, Jiangxi University of Science and Technology, Ganzhou, Jiangxi Province, China.

The methane production rate of high solid anaerobic digestion (HSAD) was poor although it was a promising technology with the advantages of small reactor, low energy consumption, and less digestate. In our research before, thermal treatment was proved to enhance HSAD's methane production rate via both batch experiments and continuous experiments of swine manure. However, the effect or investigation of thermal treatment's temperature-time combinations was not yet reported. In this study, swine manure was firstly thermally treated in 500-mL glass bottles with 400-mL work volume at 45-65 °C for 1-4 days. HSAD experiment of 10% solid content was then set up. The VS ratio of substrate to inoculum was 1:1. Thermal treatment at 45 °C (3 days), 55 °C (1 day), and 65 °C (3 days) could obtain the highest methane production rate, which was around 40% higher. Kinetics analysis suggested that the degradation of swine manure was quite different at different temperatures. Furthermore, energy assessment indicated that "thermal treatment + HSAD" had significant advantages in improving HSAD economic feasibility, because the improved methane production rate could compensate for the extra energy utilized for thermal treatment. Heat treatment at 45 °C (4 days) was preferred when the heating equipment was limited. Heat treatment at 55 °C (1 day) was preferred when the floor space and reactor volume were restricted. Heat treatment at 65°C (3 days) was preferred when the requirement of the digestate's sanitary condition is strict.
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http://dx.doi.org/10.1007/s11356-021-14926-yDOI Listing
June 2021

Molecular detection and quantification of in juice from symptomless sugarcane stalks using a real-time quantitative PCR assay.

Plant Dis 2021 Jun 18. Epub 2021 Jun 18.

Fujian Agriculture and Forestry University, Sugarcane Research Institute, 15 Shang Xia Dian Rd, Cangshan District, Fuzhou, Fujian, China, 350002;

Leaf scald, a bacterial disease caused by (Ashby) Dowson, is a major limiting factor for sugarcane production worldwide. Accurate identification and quantification of is a prerequisite for successful management of this disease. A very sensitive and robust qPCR assay was developed in this study for detection and quantification of using TaqMan probe and primers targeting a putative adenosine triphosphate-binding cassette (ABC) transporter gene (abc). The novel qPCR assay was highly specific to the 43 tested strains belonging to different pulsed-field gel electrophoresis (PFGE) groups. The detection thresholds were 100 copies/µL of plasmid DNA, 100 fg/µL of bacterial genomic DNA, and 100 CFU/ml of bacterial suspension prepared from pure culture. This qPCR assay was 100 times more sensitive than a conventional PCR assay. The pathogen was detected by qPCR in 75.1% (410/546) symptomless stalk samples, whereas only 28.4% (155/546) samples tested positive by conventional PCR. Based on qPCR data, population densities of in symptomless stalks of the same varieties differed between two sugarcane production areas in China, Beihai (Guangxi province) and Zhanjiang (Guangdong province), and no significant correlation between these populations was identified. Furthermore, no relationship was found between these populations of the pathogen in asymptomatic stalks and the resistance level of the sugarcane varieties to leaf scald. The newly developed qPCR assay proved to be highly sensitive and reliable for the detection and quantification of in sugarcane stalks.
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http://dx.doi.org/10.1094/PDIS-03-21-0468-REDOI Listing
June 2021

Therapeutic and diagnostic targeting of fibrosis in metabolic, proliferative and viral disorders.

Adv Drug Deliv Rev 2021 Jun 14:113831. Epub 2021 Jun 14.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands. Electronic address:

Fibrosis is a common denominator in many pathologies and crucially affects disease progression, drug delivery efficiency and therapy outcome. We here summarize therapeutic and diagnostic strategies for fibrosis targeting in atherosclerosis and cardiac disease, cancer, diabetes, liver diseases and viral infections. We address various anti-fibrotic targets, ranging from cells and genes to metabolites and proteins, primarily focusing on fibrosis-promoting features that are conserved among the different diseases. We discuss how anti-fibrotic therapies have progressed over the years, and how nanomedicine formulations can potentiate anti-fibrotic treatment efficacy. From a diagnostic point of view, we discuss how medical imaging can be employed to facilitate the diagnosis, staging and treatment monitoring of fibrotic disorders. Altogether, this comprehensive overview serves as a basis for developing individualized and improved treatment strategies for patients suffering from fibrosis-associated pathologies.
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http://dx.doi.org/10.1016/j.addr.2021.113831DOI Listing
June 2021

Robust k-WTA Network Generation, Analysis, and Applications to Multiagent Coordination.

IEEE Trans Cybern 2021 Jun 16;PP. Epub 2021 Jun 16.

In this article, a robust k-winner-take-all (k-WTA) neural network employing the saturation-allowed activation functions is designed and investigated to perform a k-WTA operation, and is shown to possess enhanced robustness to disturbance compared to existing k-WTA neural networks. Global convergence and robustness of the proposed k-WTA neural network are demonstrated through analysis and simulations. An application studied in detail is competitive multiagent coordination and dynamic task allocation, in which k active agents [among m (m > k)] are allocated to execute a tracking task with the static m-k ones. This is implemented by adopting a distributed k-WTA network with limited communication, aided with a consensus filter. Simulation results demonstrating the system's efficacy and feasibility are presented.
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http://dx.doi.org/10.1109/TCYB.2021.3079457DOI Listing
June 2021

Catalytic enantioselective construction of vicinal quaternary carbon stereocenters.

Chem Sci 2020 Jul 28;11(35):9341-9365. Epub 2020 Jul 28.

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University Shanghai 200062 P. R. China

This review summarizes the advances in the catalytic enantioselective construction of vicinal quaternary carbon stereocenters, introduces major synthetic strategies and discusses their advantages and limitations, highlights the application of known protocols in the total synthesis of natural products, and outlines the synthetic opportunities.
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http://dx.doi.org/10.1039/d0sc03249bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162142PMC
July 2020

MicroRNA-92b augments sorafenib resistance in hepatocellular carcinoma via targeting PTEN to activate PI3K/AKT/mTOR signaling.

Braz J Med Biol Res 2021 31;54(9):e10390. Epub 2021 May 31.

Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, China.

Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.
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http://dx.doi.org/10.1590/1414-431X2020e10390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186377PMC
June 2021

Identification of poly(ADP-ribose)polymerase 1 and 2 (PARP1/2) as targets of andrographolide using an integrated chemical biology approach.

Chem Commun (Camb) 2021 Jun 2. Epub 2021 Jun 2.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People's Republic of China.

Here, we describe the identification of PARP1/2 as direct binding proteins of andrographolide (Andro) using protein microarray, surface plasmon resonance (SPR), and enzyme activity assays. We then evaluated the proliferation inhibition, apoptosis, and cell migration effects of Andro on the MDA-MB-436 cell line in vitro. The final biological evaluation confirmed that Andro was a highly effective single agent in the MDA-MB-436 xenograft model and had a low hERG-mediated cardiac toxicity. Therefore, Andro represents the first natural product, non-amide member of a novel nanomolar-potency PARP1/2 inhibitor family.
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http://dx.doi.org/10.1039/d1cc02272eDOI Listing
June 2021

Design and Implementation of an EEG-Based Learning-Style Recognition Mechanism.

Brain Sci 2021 May 11;11(5). Epub 2021 May 11.

Department of Optical-Electrical & Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.

Existing methods for learning-style recognition are highly subjective and difficult to implement. Therefore, the present study aimed to develop a learning-style recognition mechanism based on EEG features. The process for the mechanism included labeling learners' actual learning styles, designing a method to effectively stimulate different learners' internal state differences regarding learning styles, designing the data-collection method, designing the preprocessing procedure, and constructing the recognition model. In this way, we designed and verified an experimental method that can effectively stimulate learning-style differences in the information-processing dimension. In addition, we verified the effectiveness of using EEG signals to recognize learning style. The recognition accuracy of the learning-style processing dimension was 71.2%. This result is highly significant for the further exploration of using EEG signals for effective learning-style recognition.
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http://dx.doi.org/10.3390/brainsci11050613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150355PMC
May 2021

From Design to Clinic: Engineered Nanobiomaterials for Immune Normalization Therapy of Cancer.

Adv Mater 2021 May 28:e2008094. Epub 2021 May 28.

State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.

The tumor immune microenvironment (TIME) is comprised of a complex milieu that contributes to stunting antitumor immune responses by restricting T cells to accumulate in the vicinity of the tumor. Nanomedicine-based strategies are being proposed as a salvage effort to reinvigorate antitumor immunity. Various strategies, however, often fail to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex TIME, invigorating a fervor of investigation into mechanisms underlying the TIME to resist nanomedicines. In this review article, effective nano/biomaterial-based delivery and TIME normalization approaches that promote T cell-mediated antitumor immune response will be discussed, with a focus on emerging preclinical and clinical strategies for immune normalization. Based on currently available evidence, it seems as if the ultimate success of cancer immunotherapy and nanomedicine hinges on the capacity to normalize the TIME. Here, how nanomedicines target immunosuppressive cells and signaling pathways to broaden the impact of cancer immunotherapy are explored. Acquisition of the urgently needed knowledge of nanomedicine-mediated immune normalization will guide researchers and scientists towards clinical applications of cancer immunotherapy.
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http://dx.doi.org/10.1002/adma.202008094DOI Listing
May 2021

Pharmacological targeting of TNS3 with histone deacetylase inhibitor as a therapeutic strategy in esophageal squamous cell carcinoma.

Aging (Albany NY) 2021 May 28;13(11):15336-15352. Epub 2021 May 28.

Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Histone acetylation which regulates about 2-10% of genes has been demonstrated to be involved in tumorigenesis of esophageal squamous cell carcinoma (ESCC). In this study, we investigated the treatment response of ESCC to selective histone deacetylase inhibitor (HDACi) LMK-235 and potential biomarker predicting the treatment sensitivity. We identified tensin-3 (TNS3) which was highly over-expressed in ESCC as one of the down-regulated genes in response to LMK-235 treatment. TNS3 was found positively correlated with the tumor malignancy and poor prognosis in the patients. Silencing significantly inhibited ESCC cell proliferation both and , sensitizing the treatment response to LMK-235. Our findings provide an insight into understanding the oncogenic role of TNS3 in ESCC and its clinical application for HDAC targeted therapy of ESCC.
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http://dx.doi.org/10.18632/aging.203091DOI Listing
May 2021

A Novel Review of Homocysteine and Pregnancy Complications.

Biomed Res Int 2021 6;2021:6652231. Epub 2021 May 6.

Department of Obstetrics, The First Hospital of China Medical University, Shenyang, Liaoning, China.

Homocysteine (Hct) is a substance produced in the metabolism of methionine. It is an essential type of amino acid gained from the daily diet. Methylenetetrahydrofolate reductase (MTHFR) gene mutation is related to elevated total homocysteine (tHct) expressions, in particular, among women with low folate intake. Hyperhomocysteinemia (HHct) is caused by numerous factors, such as genetic defects, lack of folic acid, vitamin B and B deficiency, hypothyroidism, drugs, aging, and renal dysfunction. Increased Hct in peripheral blood may lead to vascular illnesses, coronary artery dysfunction, atherosclerotic changes, and embolic diseases. Compared to nonpregnant women, the Hct level is lower in normal pregnancies. Recent studies have reported that HHct was associated with numerous pregnancy complications, including recurrent pregnancy loss (RPL), preeclampsia (PE), preterm delivery, placental abruption, fetal growth restriction (FGR), and gestational diabetes mellitus (GDM). Besides, it was discovered that neonatal birth weight and maternal Hct levels were negatively correlated. However, a number of these findings lack consistency. In this review, we summarized the metabolic process of Hct in the human body, the levels of Hct in different stages of normal pregnancy reported in previous studies, and the relationship between Hct and pregnancy complications. The work done is helpful for obstetricians to improve the likelihood of a positive outcome during pregnancy complications. Reducing the Hct level with a high dosage of folic acid supplements during the next pregnancy could be helpful for females who have suffered pregnancy complications due to HHct.
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http://dx.doi.org/10.1155/2021/6652231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121575PMC
May 2021

Multi- and trans-generational effects of N-butylpyridium chloride on reproduction, lifespan, and pro/antioxidant status in Caenorhabditis elegans.

Sci Total Environ 2021 Jul 10;778:146371. Epub 2021 Mar 10.

College of Ecological Technology and Engineering, Shanghai Institute of Technology, Shanghai, 201418, PR China. Electronic address:

Ionic liquids (ILs) became emerging pollutants. Their poor degradation and accumulation in organisms urged studies on the long-term effects and also the underlying mechanisms. Currently, 1-butylpyrinium chloride ([bpyr]Cl) was chosen to represent the pyridine-based ILs. Its multi-generational effects were measured on C. elegans for 14 consecutive generations (F1 to F14), and the trans-generational effects were also measured in the great-grand-children (T3 and T3') of F1 and F14. The multi-generational results from F1 to F14 showed that the effects of [bpyr]Cl on the initial and total reproduction and lifespan showed oscillation between inhibition and stimulation. Notably, hormetic effects on reproduction were observed in F7 to F10. The trans-generational effects in T3 and T3' showed different residual consequences between one generational exposure (F1) and multiple generational exposure (F14). Further biochemical analysis showed that the pro/antioxidant status also showed oscillation between inhibition and stimulation. The oscillation levels were greater in superoxide dismutase (SOD), catalase (CAT) and protein carbonyl content (PC) than those in glutathione peroxidase (GSH-Px), reactive oxygen species (ROS) and hydroxyl radical (OH). The pro/antioxidant status contributed to both multi- and trans-generational effects of [bpyr]Cl. Future studies should pay attentions to the long-term influence of ILs and also epigenetic explanations.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146371DOI Listing
July 2021

Construction of -Difluoroenol Esters through Catalytic -Selective Addition of Difluoroenoxysilanes to Ketenes.

J Org Chem 2021 Jun 17;86(11):7797-7805. Epub 2021 May 17.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.

The -site reactivity of difluoroenoxysilanes is disclosed for the first time, which enabled the direct construction of versatile -difluoroalkenes through an unprecedented highly efficient addition reaction with ketenes. A series of valuable -difluoroenol esters were achieved in good to excellent yields. The synthetic versatility of this protocol is further demonstrated by the gram-scale synthesis and good functional group tolerance.
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http://dx.doi.org/10.1021/acs.joc.1c00570DOI Listing
June 2021

Karyotypic complexity, TP53 pathogenic variants, and increased number of variants on Next-Generation Sequencing are associated with disease progression in a North American Adult T-Cell Leukemia/Lymphoma cohort.

Int J Lab Hematol 2021 May 14. Epub 2021 May 14.

Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.

Introduction: Adult T-Cell Leukemia/Lymphoma (ATLL) is an aggressive T-cell malignancy without known characteristic cytogenetic abnormalities. Recurrent mutations in TP53, APC, and epigenetic and histone-modifying genes have been identified in North American ATLL. Their roles in disease progression are not yet fully elucidated.

Methods: We studied the cytogenetic and Next-Generation Sequencing (NGS) findings of the North American ATLL cohort at our institution and compared the findings with Japanese and other North American cohorts. We also analyzed the genetic variants in TP53, APC, and histone-modifying genes and investigated the impact of their mutations on the number of mutations via NGS in ATLL.

Results: Cases with more than 6 chromosomal breaks (n = 13) had significantly shorter overall survival compared to cases with fewer chromosomal breaks (n = 7) (P = .0007). Cases with breaks on chromosome 3q (n = 4) exhibited worse survival compared to the rest of the cases (n = 16) (P = .012). Chromosomal abnormalities on 3q, 14q, 1q, 1p, and 17q are likely primary changes in ATLL based on frequency and association with prognosis. The average number of mutations via NGS was significantly higher in cases with mutations in TP53 (n = 8) (P = .020) as well as APC (n = 6) (P = .024) compared to cases without mutations in these genes. All TP53 variants were pathogenic missense and truncating mutations in COSMIC database.

Conclusion: Cytogenetic and NGS methods are useful tools to monitor disease progression in indolent ATLL and assess prognosis in aggressive ATLL.
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http://dx.doi.org/10.1111/ijlh.13577DOI Listing
May 2021

The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands.

Sci Adv 2021 May 12;7(20). Epub 2021 May 12.

Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, 35043 Marburg, Germany.

CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. The absence of SAMD1 impairs ES cell differentiation processes, leading to misregulation of key biological pathways. Together, our work establishes SAMD1 as a newly identified chromatin regulator acting at unmethylated CGIs.
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http://dx.doi.org/10.1126/sciadv.abf2229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115922PMC
May 2021

Novel GLP-1/anti-apolipoprotein B bifunctional fusion protein alleviates diabetes and diabetic complications in combination with low-intensity ultrasound.

Life Sci 2021 Aug 29;278:119549. Epub 2021 Apr 29.

Ultrasound Department of The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang Province, China. Electronic address:

Aims: To engineer and screen a novel GLP-1/anti-apolipoprotein B (apoB) bifunctional fusion protein with therapeutic potential on alleviating diabetes and diabetic complication in combination with low-intensity ultrasound.

Main Methods: Anti-apoB antibodies were screened by phage display technology and further fused to mutated GLP-1 (7-37) via light or heavy fusion to generate bifunctional fusion protein (termed aBG). The optimal design of aBG fusion protein was further confirmed by in vitro epitope competition assay and cAMP accumulation assay. Subsequently, chronic study in DIO mice were subjected to assess the long-term efficacy of screened fusion protein.

Key Findings: The selected GLP-1/anti-apoB fusion protein, aBG-8, exerted either the highest binding affinities for GLP-1R and apoB, or the greatest LDL-C uptake capacity and GLP-1R activation activity. After 60-day treatment in DIO mice, aBG-8 was proved to exert the promising improvement on hyperglycemia, hyperlipidemia, and obesity in DIO mice. Furthermore, combined therapy of aBG-8 and low-intensity ultrasound could accelerate skin wound closure in diabetic mice.

Significance: A novel long-lasting bifunctional fusion molecule, aBG-8, was designed with the enormous potential on alleviating diabetes and diabetic complications in combination with low-intensity ultrasound.
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http://dx.doi.org/10.1016/j.lfs.2021.119549DOI Listing
August 2021

Smile or Scowl? Looking at Infographic Design Through the Affective Lens.

IEEE Trans Vis Comput Graph 2021 Jun 12;27(6):2796-2807. Epub 2021 May 12.

Infographics are frequently promoted for their ability to communicate data to audiences affectively. To facilitate the creation of affect-stirring infographics, it is important to characterize and understand people's affective responses to infographics and derive practical design guidelines for designers. To address these research questions, we first conducted two crowdsourcing studies to identify 12 infographic-associated affective responses and collect user feedback explaining what triggered affective responses in infographics. Then, by coding the user feedback, we present a taxonomy of design heuristics that exemplifies the affect-related design factors in infographics. We evaluated the design heuristics with 15 designers. The results showed that our work supports assessing the affective design in infographics and facilitates the ideation and creation of affective infographics.
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http://dx.doi.org/10.1109/TVCG.2021.3074582DOI Listing
June 2021

Complex RNA Secondary Structures Mediate Mutually Exclusive Splicing of Coleoptera .

Front Genet 2021 30;12:644238. Epub 2021 Mar 30.

MOE Laboratory of Biosystems Homeostasis, Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.

Mutually exclusive splicing is an important mechanism for expanding protein diversity. An extreme example is the Down syndrome cell adhesion molecular () gene of insects, containing four clusters of variable exons (exons 4, 6, 9, and 17), which potentially generates tens of thousands of protein isoforms through mutually exclusive splicing, of which regulatory mechanisms are still elusive. Here, we systematically analyzed the variable exon 4, 6, and 9 clusters of in Coleoptera species. Through comparative genomics and RNA secondary structure prediction, we found apparent evidence that the evolutionarily conserved RNA base pairing mediates mutually exclusive splicing in the exon 4 cluster. In contrast to the fly exon 6, most exon 6 selector sequences in Coleoptera species are partially located in the variable exon region. Besides, bidirectional RNA-RNA interactions are predicted to regulate the mutually exclusive splicing of variable exon 9 of . Although the docking sites in exon 4 and 9 clusters are clade specific, the docking sites-selector base pairing is conserved in secondary structure level. In short, our result provided a mechanistic framework for the application of long-range RNA base pairings in regulating the mutually exclusive splicing of Coleoptera .
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http://dx.doi.org/10.3389/fgene.2021.644238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042237PMC
March 2021

Infantile leukemia-What factors determine its distinct biological nature? Clinicopathological study of 78 cases.

Int J Lab Hematol 2021 Apr 13. Epub 2021 Apr 13.

Department of Pathology, Duke University Medical Center, Durham, NC, USA.

Introduction: Infantile leukemia encompasses a heterogeneous group which needs stratifying for treatment selection.

Methods: We collected 78 cases of infantile leukemia and retrospectively analyzed their clinicopathological data.

Results: Infantile leukemia featured a ratio of acute myeloid leukemia (AML) to B-lymphoblastic leukemia (B-ALL) of 1:2, with a better survival for AML than B-ALL (median survival 36 vs 24 months). When stratified by age, "early" infantile B-ALL (2-6 months) showed a high rate of KMT2A rearrangement (100%), similar to the rate seen in congenital B-ALL (1 month) (100%) and higher than seen in "late" infantile B-ALL (≥7 months) (68%). The three categories of infantile B-ALL exhibited an age-dependent increase in survival (median survival 8.5, 24, and >24 months, respectively). The age-dependent survival benefit remained after excluding the cases negative for KMT2A rearrangement. Conversely, infantile AML lacked an age-dependent pattern of survival.

Conclusion: The clinical outcome of infantile leukemia depends on the type of leukemia. Given the age-dependent survival, infantile B-ALL can be divided into three subcategories.
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http://dx.doi.org/10.1111/ijlh.13540DOI Listing
April 2021

Long-term Survival Comparison of Repeated Breast-conserving Surgery Versus Mastectomy for Patients with DCIS with Ipsilateral Breast Tumor Recurrence: A Real-world Longitudinal Study.

Clin Breast Cancer 2021 Mar 5. Epub 2021 Mar 5.

Department of the Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China. Electronic address:

Background: Although patients diagnosed with ductal carcinoma in situ (DCIS) harbor excellent overall survival (OS) after breast-conserving therapy, the evidence regarding to surgical management for ipsilateral breast tumor recurrence (IBTR) is scarce. This study aimed to assess the prognosis of repeated breast-conserving surgery (BCS) versus mastectomy for IBTR in DCIS survivors.

Materials And Methods: Herein, 5344 DCIS cases with IBTR were identified during 702,748 person-years of follow-up, 3532 (66.09%) received mastectomy, and 1812 (33.91%) received repeated BCS. Cox regression and competing risk regression were employed to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and breast cancer-specific survival (BCSS), which was respectively calculated within spontaneous and matched cohorts.

Results: After adjustment for confounders, no statistically significant survival difference was observed between the repeated BCS and mastectomy for patients with DCIS with IBTR. The stratified analyses further revealed that patients with DCIS with IBTR receiving repeated BCS combined with radiation therapy were associated with both superior OS (HR, 0.79; CI, 0.64-0.98; P = .04) and BCSS (HR, 0.54; CI, 0.33-0.90; P = .02) compared with counterparts undergoing mastectomy. Furthermore, patients with DCIS who were age older than 60 years at IBTR diagnosis benefit from repeated BCS with radiotherapy (HR, 0.44; CI, 0.24-0.84; P = .01) than mastectomy.

Conclusion: We suggest that repeated BCS with radiation therapy deserves consideration when DCIS survivors suffered IBTR. The choice of surgical management should be tailored based on patients' age at IBTR diagnosis and size of recurrent disease.
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http://dx.doi.org/10.1016/j.clbc.2021.02.012DOI Listing
March 2021

Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia.

Neuron 2021 05 7;109(10):1657-1674.e7. Epub 2021 Apr 7.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA. Electronic address:

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease and directly influences tauopathy and tau-mediated neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In the brain, apoE is produced and secreted primarily by astrocytes and by activated microglia. The cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We generated P301S Tau/Aldh1l1-CreERT2/apoE3 or Tau/Aldh1l1-CreERT2/apoE4 mice. At 5.5 months of age, after the onset of tau pathology, we administered tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic APOE4 markedly reduced tau-mediated neurodegeneration and decreased phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types, with astrocytic APOE4 removal decreasing disease-associated gene signatures in neurons, oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements, suggesting a key role for astrocytic apoE in synaptic degeneration.
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http://dx.doi.org/10.1016/j.neuron.2021.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141024PMC
May 2021

Purification, structural characterization and immunostimulatory activity of polysaccharides from Umbilicaria esculenta.

Int J Biol Macromol 2021 Jun 30;181:743-751. Epub 2021 Mar 30.

Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China; School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, People's Republic of China. Electronic address:

In this study, an active component UP1-1 was isolated from Chinese Huangshan Umbilicaria esculenta via hot water extraction and purified by anion-exchange and gel-filtration chromatography. UP1-1 mainly composed of galactose, mannose and glucose in a molar ratio of 0.8:1.0:4.6 with an average molecular weight of 281 kDa. Methylation analysis of UP1-1 revealed the major glycosidic bonds comprised 1,6-linked Glcp, 1,4-linked Glcp, t-linked Glcp, 1,3,6-linked Manp, 1,3-linked Galp, t-linked Galp at the ratio of 2.28:0.38:0.32:0.63:0.25:0.29. Structural analysis results revealed that the backbone of UP1-1 consisted of →6)-β-D-Glcp-(1→, →6)-β-D-Manp-(1→, →4)-β-D-Glcp-(1 → residues with side chains of →3)-β-D-Galp-(1→, β-D-Galp-(1 → and β-D-Glcp-(1 → branches located at O-3 position of →6)-β-D-Manp-(1→. Immunostimulatory activity tests showed that UP1-1 could promote the phagocytic activity and NO production of RAW 264.7 cells in a dose-dependent manner. UP1-1 could significantly improve the proliferation effect of RAW 264.7 cells at the concentration of 50 μg/mL. Thus, UP1-1 exerted good immunostimulatory activity, suggesting that UP1-1 has a great potential application in pharmacological industry.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.03.176DOI Listing
June 2021

Mutational spectrum and precision oncology for biliary tract carcinoma.

Theranostics 2021 4;11(10):4585-4598. Epub 2021 Mar 4.

Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China.

The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included (53%), (26%), (18%), (14%) and (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. and mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.
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http://dx.doi.org/10.7150/thno.56539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978308PMC
March 2021

Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.

Acta Neuropathol 2021 05 16;141(5):697-708. Epub 2021 Mar 16.

MRC Laboratory of Molecular Biology, Cambridge, UK.

Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.
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http://dx.doi.org/10.1007/s00401-021-02294-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043864PMC
May 2021

Metagenomic sequencing revealed the potential of banknotes as a repository of microbial genes.

BMC Genomics 2021 Mar 11;22(1):173. Epub 2021 Mar 11.

Institute of Applied Genomics, Fuzhou University, No.2 Xueyuan Road, Fuzhou, 350108, China.

Background: Genetic resources are important natural assets. Discovery of new enzyme gene sequences has been an ongoing effort in biotechnology industry. In the genomic age, genomes of microorganisms from various environments have been deciphered. Increasingly, it has become more and more difficult to find novel enzyme genes. In this work, we attempted to use the easily accessible banknotes to search for novel microbial gene sequences.

Results: We used high-throughput genomic sequencing technology to comprehensively characterize the diversity of microorganisms on the US dollars and Chinese Renminbis (RMBs). In addition to finding a vast diversity of microbes, we found a significant number of novel gene sequences, including an unreported superoxide dismutase (SOD) gene, whose catalytic activity was further verified by experiments.

Conclusions: We demonstrated that banknotes could be a good and convenient genetic resource for finding economically valuable biologicals.
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http://dx.doi.org/10.1186/s12864-021-07424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953773PMC
March 2021

Simultaneous Inhibition of LSD1 and TGF-B Enables Eradication of Poorly Immunogenic Tumors with anti-PD-1 Treatment.

Cancer Discov 2021 Mar 9. Epub 2021 Mar 9.

Department of Medicine, Boston Children's Hospital

Epigenetic regulators are a class of promising targets in the combination with immune checkpoint inhibitors for cancer treatment, but the impact of the broad effects of perturbing epigenetic regulators on tumor immunotherapy remains to be fully explored. Here we show that ablation of the histone demethylase LSD1 in multiple tumor cells induces TGF-B expression, which exerts an inhibitory effect on T cell immunity through suppressing the cytotoxicity of intratumoral CD8+ T cells and consequently dampens the antitumor effect of LSD1 ablation-induced T cell infiltration. Importantly, concurrent depletion of LSD1 and TGF-B in combination with PD-1 blockade significantly increases both CD8+ T cell infiltration and cytotoxicity, leading to eradication of poorly immunogenic tumors and a long-term protection from tumor re-challenge. Thus, combining LSD1 inhibition with blockade of TGF-B and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0017DOI Listing
March 2021

Primary Effusion Lymphoma: A Clinicopathological Study of 70 Cases.

Cancers (Basel) 2021 Feb 19;13(4). Epub 2021 Feb 19.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26-91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses only, and eight (11%) had both effusion and extracavitary disease. The lymphoma cells showed plasmablastic, immunoblastic, or anaplastic morphology. All 70 (100%) cases were positive for HHV8. Compared with effusion-only PEL, patients with extracavitary-only PEL were younger (median age, 42 vs. 52 years, = 0.001), more likely to be HIV-positive (88.9% vs. 68.6%, = 0.06) and EBV-positive (76.9% vs. 51.9%, = 0.06), and less often positive for CD45 (69.2% vs. 96.2%, = 0.01), EMA (26.7% vs. 100%, = 0.0005), and CD30 (60% vs. 81.5%, = 0.09). Of 52 (50%) patients with clinical follow-up, 26 died after a median follow-up time of 40.0 months (range 0-96), and the median overall survival was 42.5 months. The median OS for patients with effusion-only and with extracavitary-only PEL were 30.0 and 37.9 months, respectively ( = 0.34), and patients with extracavitary-only PEL had a lower mortality rate at the time of last follow-up (35% vs. 61.5%, = 0.07). The median OS for HIV-positive and HIV-negative patients were 42.5 and 6.8 months, respectively ( = 0.57), and they had a similar mortality rate of 50% at last follow-up. In conclusion, patients presenting with effusion-only versus extracavitary-only disease are associated with different clinicopathologic features. PEL is an aggressive lymphoma with a poor prognosis, regardless of extracavitary presentation or HIV status.
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http://dx.doi.org/10.3390/cancers13040878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922633PMC
February 2021