Publications by authors named "Dan Lu"

473 Publications

Students' Perceptions of a Blended Learning Environment to Promote Critical Thinking.

Authors:
Dan Lu

Front Psychol 2021 25;12:696845. Epub 2021 Jun 25.

School of Foreign Languages, Northeast Normal University, Changchun, China.

Critical thinking is considered as one of the indispensable skills that must be possessed by the citizens of modern society, and its cultivation with blended learning has drawn much attention from researchers and practitioners. This study proposed the construction of a blended learning environment, where the pedagogical, social, and technical design was directed to fostering critical thinking. The purpose of the study was to find out students' perceptions of the learning environment concerning its design and its influence on their critical thinking. Adopting the mixed method, the study used questionnaire and interview as the instruments for data collection. The analysis of the data revealed that the students generally held positive perceptions of the environment, and they believed that the blended learning environment could help promote their critical thinking in different aspects.
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http://dx.doi.org/10.3389/fpsyg.2021.696845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267247PMC
June 2021

Clinical Characteristics and Resistance Patterns of Pseudomonas aeruginosa Isolated From Combat Casualties.

Mil Med 2021 Jul 1. Epub 2021 Jul 1.

Brooke Army Medical Center, JBSA Fort Sam Houston, TX 78234, USA.

Introduction: Multidrug-resistant (MDR) Gram-negative infections complicate care of combat casualties. We describe the clinical characteristics, resistance patterns, and outcomes of Pseudomonas aeruginosa infections in combat casualties.

Methods: Combat casualties included in the Trauma Infectious Disease Outcomes Study with infections with and without P. aeruginosa isolation during initial hospitalization were compared. Pseudomonas aeruginosa from initial wound, blood, and serial isolates (≥7 days from previous isolate) collected from June 2009 through February 2014 was subjected to antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and whole genome sequencing for assessing clonality. Multidrug resistance was determined using the CDC National Healthcare Safety Network definition.

Results: Of 829 combat casualties with infections diagnosed during initial hospitalization, 143 (17%) had P. aeruginosa isolated. Those with P. aeruginosa were more severely injured (median Injury Severity Score 33 [interquartile range (IQR) 27-45] vs 30 [IQR 18.5-42]; P < .001), had longer hospitalizations (median 58.5 [IQR 43-95] vs 38 [IQR 26-56] days; P < .001), and higher mortality (6.9% vs 1.5%; P < .001) than those with other organisms. Thirty-nine patients had serial P. aeruginosa isolation (median 2 subsequent isolates; IQR: 1-5), with decreasing antimicrobial susceptibility. Ten percent of P. aeruginosa isolates were MDR, associated with prior exposure to antipseudomonal antibiotics (P = .002), with amikacin and colistin remaining the most effective antimicrobials. Novel antimicrobials targeting MDR Gram-negative organisms were also examined, and 100% of the MDR P. aeruginosa isolates were resistant to imipenem/relabactam, while ceftazidime/avibactam and ceftolozane/tazobactam were active against 35% and 56% of the isolates, respectively. We identified two previously unrecognized P. aeruginosa outbreaks involving 13 patients.

Conclusions: Pseudomonas aeruginosa continues to be a major cause of morbidity, affecting severely injured combat casualties, with emergent antimicrobial resistance upon serial isolation. Among MDR P. aeruginosa, active antimicrobials remain the oldest and most toxic. Despite ongoing efforts, outbreaks are still noted, reinforcing the crucial role of antimicrobial stewardship and infection control.
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http://dx.doi.org/10.1093/milmed/usab259DOI Listing
July 2021

Seasonal changes in GPP/SIF ratios and their climatic determinants across the Northern Hemisphere.

Glob Chang Biol 2021 Jun 29. Epub 2021 Jun 29.

Department of Biology and Graduate Degree Program in Ecology, Colorado State University, Fort Collins, CO, USA.

Satellite-derived sun-induced chlorophyll fluorescence (SIF) has been increasingly used for estimating gross primary production (GPP). However, the relationship between SIF and GPP has not been well defined, impeding the translation of satellite observed SIF to GPP. Previous studies have generally assumed a linear relationship between SIF and GPP at daily and longer time scales, but support for this assumption is lacking. Here, we used the GPP/SIF ratio to investigate seasonal variations in the relationship between SIF and GPP over the Northern Hemisphere (NH). Based on multiple SIF products and MODIS and FLUXCOM GPP data, we found strong seasonal hump-shaped patterns for the GPP/SIF ratio over northern latitudes, with higher values in the summer than in the spring or autumn. This hump-shaped GPP/SIF seasonal variation was confirmed by examining different SIF products and was evident for most vegetation types except evergreen broadleaf forests. The seasonal amplitude of the GPP/SIF ratio decreased from the boreal/arctic region to drylands and the tropics. For most of the NH, the lowest GPP/SIF values occurred in October or September, while the maximum GPP/SIF values were evident in June and July. The most pronounced seasonal amplitude of GPP/SIF occurred in intermediate temperature and precipitation ranges. GPP/SIF was positively related to temperature in the early and late parts of the growing season, but not during the peak growing months. These shifting relationships between temperature and GPP/SIF across different months appeared to play a key role in the seasonal dynamics of GPP/SIF. Several mechanisms may explain the patterns we observed, and future research encompassing a broad range of climate and vegetation settings is needed to improve our understanding of the spatial and temporal relationships between SIF and GPP. Nonetheless, the strong seasonal variation in GPP/SIF we identified highlights the importance of incorporating this behavior into SIF-based GPP estimations.
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http://dx.doi.org/10.1111/gcb.15775DOI Listing
June 2021

Engineering Single-Atomic Iron-Catalyst-Integrated 3D-Printed Bioscaffolds for Osteosarcoma Destruction with Antibacterial and Bone Defect Regeneration Bioactivity.

Adv Mater 2021 Jun 19:e2100150. Epub 2021 Jun 19.

Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University School of Medicine, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center of Interventional Medicine, Shanghai, 200072, P. R. China.

Effective antitumor therapeutics with distinctive bactericidal and osteogenic properties are in high demand for comprehensive osteosarcoma treatment. Here, a "scaffold engineering" strategy that integrates highly active single-atomic iron catalysts (FeSAC) into a 3D printed bioactive glass (BG) scaffold is reported. Based on the atomically dispersed iron species within the catalysts, the engineered FeSAC displays prominent Fenton catalytic activity to generate toxic hydroxyl radicals (•OH) in response to the microenvironment specific to osteosarcoma. In addition, the constructed FeSAC-BG scaffold can serve as a sophisticated biomaterial platform for efficient osteosarcoma ablation, with concomitant bacterial sterilization via localized hyperthermia-reinforced nanocatalytic therapeutics. The destruction of the osteosarcoma, as well as the bacterial foci, can be achieved, further preventing susceptible chronic osteomyelitis during osteogenesis. In particular, the engineered FeSAC-BG scaffold is identified with advances in accelerated osteoconduction and osteoinduction, ultimately contributing to the sophisticated therapeutics and management of osteosarcoma. This work broadens the biomedical potential of single-atom catalysts and offers a comprehensive clinically feasible strategy for overall osteosarcoma therapeutics, bacterial inhibition, and tissue regeneration.
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http://dx.doi.org/10.1002/adma.202100150DOI Listing
June 2021

Biological evaluation of mitochondria targeting small molecules as potent anticancer drugs.

Bioorg Chem 2021 Jun 3;114:105055. Epub 2021 Jun 3.

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University (SJTU), No. 800 Dongchuan Rd. Minhang District, Shanghai, 200240, PR China; SJTU-Agilent Technologies Joint Laboratory for Pharmaceutical Analysis, School of Pharmacy, Shanghai Jiao Tong University (SJTU), No. 800 Dongchuan Rd. Minhang District, Shanghai, 200240, PR China. Electronic address:

Cancer therapy targets specific metabolic pathways or a single gene. This may result in low therapeutic effects due to drug selectivity and drug resistance. Recent studies revealed that the mitochondrial membrane potential and transmembrane permeability of cancerous mitochondria are differed from normal mitochondria. Thus, chemotherapy targeting cancerous mitochondria could be an innovative and competent strategy for cancer therapy. Previously, our work with a novel group of mitochondria targeting small molecules presented promising inhibitory capability toward various cancer cell lines and suppressed adenosine triphosphate (ATP) generation. Therefore, it is critical to understand the anticancer effect and targeting mechanism of these small molecules. This study investigated the inhibitory activity of mitochondria targeting small molecules with human cervical cancer cells - HeLa to further explore their therapeutic potential. HeLa cells were exposed to 10 µM of synthesized compounds and presented elevation in intracellular reactive oxygen species (ROS) level, impaired mitochondrial membrane potential and upregulation of apoptosis as well as necrosis. In vivo, HeLa cell tumor-bearing BALB/c nude mice were treated with mitochondria targeting small molecules for 12 days consecutively. Throughout this chemotherapy study, no deleterious side effects nor the appearance of toxicity was observed. Furthermore, mitochondria targeting small molecules treated groups exhibited significant down-regulation with both tumor volume and tumor weight compared to the Doxorubicin (DOX) treated group. Thus, inhibition of mitochondrial ATP synthesis, activation of intracellular ROS production, down-regulation of mitochondrial membrane potential and upregulation of apoptosis and necrosis rates are the indications of cancer therapy. In this work, we examined the anticancer capability of four mitochondria targeting small molecules in vitro and in vivo, and demonstrated a novel therapeutic approach in cancer therapy with tremendous potential.
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http://dx.doi.org/10.1016/j.bioorg.2021.105055DOI Listing
June 2021

Design, synthesis and biological evaluation of novel thiazole-derivatives as mitochondrial targeting inhibitors of cancer cells.

Bioorg Chem 2021 May 25;114:105015. Epub 2021 May 25.

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China; SJTU-Agilent Technologies Joint Laboratory for Pharmaceutical Analysis, School of Pharmacy, Shanghai Jiao Tong University (SJTU), No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China. Electronic address:

Mitochondria are pivotal energy production sources for cells to maintain necessary metabolism activities. Targeting dysfunctional mitochondrial features has been a hotspot for mitochondrial-related disease researches. Investigation with cancerous mitochondrial metabolism is a continuing concern within tumor therapy. Herein, we set out to assess the anti-cancer activities of a novel family of TPP-thiazole derivatives based on our earlier research on mitochondrial targeting agents. Specifically, we designed and synthesized a series of TPP-thiazole derivatives and revealed by the MTT assay that most synthesized compounds effectively inhibited three cancer cell lines (HeLa, PC3 and MCF-7). After structure modifications, we explored the SAR relationships and identified the most promising compound R13 (IC of 5.52 μM) for further investigation. In the meantime, we performed ATP production assay to assess the selected compounds inhibitory effect on HeLa cells energy production. The results displayed the test compounds significantly restrained ATP production of cancer cells. Overall, we have designed and synthesized a series of compounds which exhibited significant cytotoxicity against cancer cells and effectively inhibited mitochondrial energy production.
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http://dx.doi.org/10.1016/j.bioorg.2021.105015DOI Listing
May 2021

Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species.

Cell 2021 06 24;184(13):3438-3451.e10. Epub 2021 May 24.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.
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http://dx.doi.org/10.1016/j.cell.2021.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142884PMC
June 2021

Synthesis, biological evaluation and molecular modeling of benzofuran piperidine derivatives as Aβ antiaggregant.

Eur J Med Chem 2021 May 25;222:113541. Epub 2021 May 25.

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University (SJTU), Shanghai, China; SJTU-Agilent Technologies Joint Laboratory for Pharmaceutical Analysis, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China; Academy of Pharmacy, Xi'an Jiaotong - Liverpool University, Suzhou, 215123, China. Electronic address:

A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aβ antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aβ antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aβ peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC = 61 μM and self induced Aβ aggregation 45.45%), to increase its activity toward AD related targets. The most interesting multifunctional Aβ antiaggregants were compounds 3a, 3h and 3i, highlighting 3h as potent Aβ antiaggregant and good antiacetylholinesterase inhibitor (self induced Aβ aggregation 57.71% and hAChE IC = 21 μM), with good neuroprotective and antioxidant activity. In addition, these three most promising compounds prevent intracellular reactive oxygen species (ROS) formation and cell apoptosis induced by Aβ peptides in SH-SY5Y cells. Molecular docking studies were also accomplished to understand the binding interaction of these compounds on Aβ monomer, Aβ fibril and AChE. Based on all data, compounds 3a, 3h and 3i were concluded as potent multifunctional Aβ antiaggregant, useful candidate for the treatment of AD.
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http://dx.doi.org/10.1016/j.ejmech.2021.113541DOI Listing
May 2021

Spatiotemporal Changes of Ecosystem Service Value Determined by National Land Space Pattern Change: A Case Study of Fengdu County in The Three Gorges Reservoir Area, China.

Int J Environ Res Public Health 2021 05 9;18(9). Epub 2021 May 9.

School of Geographical Sciences, Southwest University, Chongqing 400045, China.

Exploring the spatiotemporal change characteristics of ecosystem service value (ESV) under the influence of national land space pattern (NLSP) changes is of great significance for promoting the rational use of land resources and the optimization of ecosystems. In this study, Fengdu County in the Three Gorges Reservoir Area was selected as a case study. We analyzed the changes in NLSP using land use data from 1990, 2000, 2010 and 2018. Then, we used the equivalent factor method and exploratory spatial data analysis method to explore the spatiotemporal change characteristics of the ESV of Fengdu County. The results show that: (1) From 1990 to 2018, the changes in NLSP in Fengdu County generally manifested in the transformation of agricultural space into urban space and ecological space; (2) The spatiotemporal change of ESV is a process that positively responds to the increase in ecological space and negatively responds to the expansion of urban space. From 1990 to 2018, the total ESV of Fengdu County showed a trend of continuous growth, with a total increase of CNY 11.10 × 10, and the change rate was 9.33%. The ESV gain area is mainly located along the Yangtze River and the southernmost part of the county, and the loss area is mainly located near the south bank of the Yangtze River; (3) ESV and its changes in Fengdu County have a significant positive spatial autocorrelation. The cold and hot spots of ESV change are mainly distributed along the Yangtze River and to the south of the Yangtze River. Therefore, it is suggested to integrate ESV as an important indicator into the decision-making of national land space planning. At the same time, it is necessary to strengthen the intensive use of urban space and protect the important ecological space from decreasing. Our study results provide useful insights for the development of regional NLS management and environmental protection policies. However, it is worth noting that the results of this paper are more applicable to areas where the terrain is dominated by mountains.
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http://dx.doi.org/10.3390/ijerph18095007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126005PMC
May 2021

Methods for Determining Myc-Induced Apoptosis.

Methods Mol Biol 2021 ;2318:209-229

Department of Biochemistry, University of Cambridge, Cambridge, UK.

Although many oncoproteins promote cell growth and proliferation, some also possess the potential to induce cell cycle arrest or cell death by apoptosis. Elevated and deregulated expression of the Myc protein promotes apoptosis in both cultured cells and in some tissues in vivo. Here we describe techniques to detect Myc-induced apoptosis in vitro using flow cytometry, microscopy, and immunoblotting, and in vivo using immunohistochemical staining, immunoblotting, and analysis of RNA expression.
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http://dx.doi.org/10.1007/978-1-0716-1476-1_10DOI Listing
January 2021

EphA4 is highly expressed in the atria of heart and its deletion leads to atrial hypertrophy and electrocardiographic abnormalities in rats.

Life Sci 2021 Aug 8;278:119595. Epub 2021 May 8.

Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medicine College, Chinese Academy of Medical Sciences, Beijing 100021, China. Electronic address:

Aims: EphA4 is a member of the Eph receptor family, and expressed mainly in central nervous system (CNS), which is involved in CNS development and multiple diseases. Due to the variability in EphA4 expression, we wondered if EphA4 is expressed in other tissues, and what role does EphA4 play?

Materials And Methods: We generated an EphA4 knockout (KO) rat line with red fluorescent marker protein encoded by the mCherry cassette inserted downstream of the EphA4 promoter as a reporter. Using this system, we observed high expression of EphA4 in the heart atria and in the brain.

Key Findings: EphaA4 KO rats (EphA4) developed obvious atrial hypertrophy with an increased atria-to-heart weight ratio and atrial cardiomyocyte cross-sectional area at six months of age. EphA4 rats had reduced atrial end diastolic volume (EDV), atrial ejection fraction (EF) and left ventricular EF. They also exhibited increased amplitude of QRS complexes and QT intervals, with invisible p waves. RNA sequencing revealed that EphA4 KO altered the transcription of multiple genes involved in regulation of transcription and translation, ion binding, metabolism and cell adhesion. Deletion of EphA4 reduced IGF1 mRNA and protein expression, which is involved in cardiac remodeling.

Significance: Our data demonstrated that EphA4 was highly expressed in the atria and its deletion caused atrial dysfunction. Our findings also suggested that the EphA4 KO rat could be a potential model for studies on atrial remodeling.
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http://dx.doi.org/10.1016/j.lfs.2021.119595DOI Listing
August 2021

Supracricoid partial laryngectomy with cricohyoidoepiglottopexy for patients with laryngeal cicatricial stenosis: Safety and efficacy.

Head Neck 2021 May 4. Epub 2021 May 4.

Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China.

Background: We assessed the safety and efficacy of supracricoid partial laryngectomy with cricohyoidoepiglottopexy (SCL-CHEP) in patients with laryngeal cicatricial stenosis.

Methods: Sixteen patients receiving SCL-CHEP for severe laryngeal cicatricial stenosis between 2017 and 2018 were reviewed. Decannulation rate and tracheostomy closure time were used to evaluate efficacy. The Voice Handicap Index-10 (VHI-10), Voice-related Quality of Life (V-RQOL) scale and Grade, Roughness, Breathiness, Asthenia, and Strain (GRBAS) scale were used to assess vocal function. Fiberoptic endoscopic evaluation of swallowing (FEES) was performed and the Penetration-Aspiration Scale (PAS), Eating Assessment Tool-10 (EAT-10), and Swallow Quality of Life Questionnaire (SWAL-QOL) were used to assess swallowing function.

Results: Thirteen patients (81.25%) were decannulated successfully. The average tracheostomy closure time was 45.15 days. There was no observed postoperative complications or recurrence of stenosis. VHI-10 and V-RQOL scores showed significantly improved V-RQOL (p < 0.05). FEES-PAS, EAT-10, and SWAL-QOL showed no swallowing function damage.

Conclusions: SCL-CHEP is effective and safe for patients with severe laryngeal cicatricial stenosis. Accurate pre-procedure evaluation is especially important for patient selection and surgical success.
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http://dx.doi.org/10.1002/hed.26734DOI Listing
May 2021

Dysregulation of autophagy-associated microRNAs in condyloma acuminatum.

Infect Genet Evol 2021 Apr 24;93:104878. Epub 2021 Apr 24.

Department of Dermatology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510630, China; Dermatology Institute of Jinan University, Jinan University, Guangzhou 510630, China. Electronic address:

Condyloma acuminatum, which is caused by low-risk human papillomavirus (lrHPV) infection, is one of the most common sexually transmitted diseases. Autophagy is thought to be associated with condyloma acuminatum, but how the autophagy process is regulated remains unclear. MicroRNAs (miRNAs) are important regulators of gene transcription that play a central role in many biological processes, including autophagy and viral infection. This study was designed to identify autophagy-related miRNAs and their targets in condyloma acuminatum and to validate their expression. The levels of the autophagy proteins microtubule-associated protein 1 light chain 3 (LC3) and P62/SQSTM1 (P62) were abnormally increased in the local lesion tissue of condyloma acuminatum patients compared with healthy controls. MiRNAs and their target mRNAs in condyloma acuminatum patients were analyzed by bioinformatics. Eighty-one differentially expressed miRNAs were identified, of which 56 were downregulated and 25 were upregulated. Two of the differentially expressed miRNAs associated with autophagy, miRNA-30a-5p and miRNA-514a-3p, were analyzed further, and their target genes were identified as autophagy-related protein (Atg) 5 and Atg12 and Atg3 and Atg12, respectively. The expression levels of miRNA-30a-5p and miRNA-514a-3p were decreased and those of Atg5, Atg12 and Atg3 were increased in condyloma acuminatum patients compared with healthy controls. In addition, miRNA-30a-5p and miRNA-514a-3p expression correlated with the proliferation index Ki-67 in condyloma acuminatum. Taken together, our results suggest that the changes in autophagy levels in patients with condyloma acuminatum may be related to the changes in miRNA-30a-5p and miRNA-514a-3p expression. This study provides a theoretical basis for identifying new mechanisms that link miRNAs, HPV infection and host autophagy in vivo.
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http://dx.doi.org/10.1016/j.meegid.2021.104878DOI Listing
April 2021

Model-Informed Therapeutic Dose Optimization Strategies for Antibody-Drug Conjugates in Oncology: What Can We Learn From US Food and Drug Administration-Approved Antibody-Drug Conjugates?

Clin Pharmacol Ther 2021 Apr 26. Epub 2021 Apr 26.

Genentech Inc., South San Francisco, California, USA.

Antibody-drug conjugates (ADCs) combine the specificity of an antibody with the cytotoxicity of a chemical agent. They represent a rapidly evolving area of oncology drug development and hold significant promise. There are currently nine ADCs on the market, more than half of which gained US Food and Drug Administration approval more recently, since 2019. Despite their enormous promise, the therapeutic window for these ADCs remains relatively narrow, especially when compared with other oncology drugs, such as targeted therapies or checkpoint inhibitors. In this review, we provide a detailed overview of the five dosing regimen optimization strategies that have been leveraged to broaden the therapeutic window by mitigating the safety risks while maintaining efficacy. These include body weight cap dosing; treatment duration capping; dose schedule (e.g., dosing frequency and dose fractionation); response-guided dosing recommendations; and randomized dose-finding. We then discuss how the lessons learned from these studies can inform ADC development going forward. Informed application of these dosing strategies should allow researchers to maximize the safety and efficacy for next-generation ADCs.
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http://dx.doi.org/10.1002/cpt.2278DOI Listing
April 2021

Effect of Enzymatic Hydrolysis on the Zinc Binding Capacity and Gastrointestinal Stability of Peptides Derived From Pumpkin (.) Seeds.

Front Nutr 2021 31;8:647782. Epub 2021 Mar 31.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China.

Zinc is a crucial micronutrient for maintaining body immune system and metabolism function. However, insufficient intake from diet may lead to zinc deficiency and impair normal body function. In addition, conventional zinc salts supplementation has the disadvantage of low bioavailability since the zinc ions may be easily chelated by dietary fiber or phytate commonly found in diets rich in plants, and form precipitates that cannot be absorbed. Therefore, the objective of the present study is to prepare pumpkin seed derived peptides and to evaluate the effect of structure and surface properties on the zinc binding behavior of the pumpkin seed protein hydrolysate (PSPH), as well as their gastrointestinal stability. Briefly, different PSPHs were prepared using enzymatic hydrolysis method with bromelain, papain, flavourzyme, alcalase, and pepsin. The particle size, zeta potential, surface hydrophobicity, degree of hydrolysis, ATR-FTIR spectra, and zinc binding capacity were determined. The representative samples were chosen to characterize the binding energy and surface morphology of PSPH-Zn. At last, the gastrointestinal stability of PSPH and PSPH-Zn were evaluated. Our results showed that peptides hydrolyzed by papain had the largest average molecular weight, smallest particle size, highest hydrophobicity, and the greatest zinc binding capacity. Zinc showed better gastrointestinal stability in PSPHs chelates than in its salt. Meanwhile, PSPH-Zn with higher zinc binding capacity showed better stability. The result of this study indicated pumpkin seed hydrolyzed by papain may be used as a potential source for zinc fortification. The findings in this study may provide important implications for developing plant-based zinc chelating peptides.
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http://dx.doi.org/10.3389/fnut.2021.647782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044297PMC
March 2021

Comparative Analysis of Chemical Constituents in Different Parts of Lotus by UPLC and QToF-MS.

Molecules 2021 Mar 25;26(7). Epub 2021 Mar 25.

School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China.

Six parts of lotus (seeds, leaves, plumule, stamens, receptacles and rhizome nodes) are herbal medicines that are listed in the Chinese Pharmacopoeia. Their indications and functions have been confirmed by a long history of clinical practice. To fully understand the material basis of clinical applications, UPLC-QToF-MS combined with the UNIFI platform and multivariate statistical analysis was used in this study. As a result, a total of 171 compounds were detected and characterized from the six parts, and 23 robust biomarkers were discovered. The method can be used as a standard protocol for the direct identification and prediction of the six parts of lotus. Meanwhile, these discoveries are valuable for improving the quality control method of herbal medicines. Most importantly, this was the first time that alkaloids were detected in the stamen, and terpenoids were detected in the cored seed. The stamen is a noteworthy part because it contains the greatest diversity of flavonoids and terpenoids, but research on the stamen is rather limited.
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http://dx.doi.org/10.3390/molecules26071855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036816PMC
March 2021

Pharm-AutoML: An open-source, end-to-end automated machine learning package for clinical outcome prediction.

CPT Pharmacometrics Syst Pharmacol 2021 May 2;10(5):478-488. Epub 2021 May 2.

Genentech Inc, South San Francisco, California, USA.

Although there is increased interest in utilizing machine learning (ML) to support drug development, technical hurdles associated with complex algorithms have limited widespread adoption. In response, we have developed Pharm-AutoML, an open-source Python package that enables users to automate the construction of ML models and predict clinical outcomes, especially in the context of pharmacological interventions. In particular, our approach streamlines tedious steps within the ML workflow, including data preprocessing, model tuning, model selection, results analysis, and model interpretation. Moreover, our open-source package helps to identify the most predictive ML pipeline among defined search spaces by selecting the best data preprocessing strategy and tuning the ML model hyperparameters. The package currently supports multiclass classification tasks, and additional functions are being developed. Using a set of five publicly available biomedical datasets, we show that our Pharm-AutoML outperforms other ML frameworks, including H2O with default settings, by demonstrating improved predictive accuracy of classification. We further illustrate how model interpretation methods can be utilized to help explain the fine-tuned ML pipeline to end users. Pharm-AutoML provides both novice and expert users improved clinical predictions and scientific insights.
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http://dx.doi.org/10.1002/psp4.12621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129712PMC
May 2021

Raw biomass electroreforming coupled to green hydrogen generation.

Nat Commun 2021 03 31;12(1):2008. Epub 2021 Mar 31.

School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore.

Despite the tremendous progress of coupling organic electrooxidation with hydrogen generation in a hybrid electrolysis, electroreforming of raw biomass coupled to green hydrogen generation has not been reported yet due to the rigid polymeric structures of raw biomass. Herein, we electrooxidize the most abundant natural amino biopolymer chitin to acetate with over 90% yield in hybrid electrolysis. The overall energy consumption of electrolysis can be reduced by 15% due to the thermodynamically and kinetically more favorable chitin oxidation over water oxidation. In obvious contrast to small organics as the anodic reactant, the abundance of chitin endows the new oxidation reaction excellent scalability. A solar-driven electroreforming of chitin and chitin-containing shrimp shell waste is coupled to safe green hydrogen production thanks to the liquid anodic product and suppression of oxygen evolution. Our work thus demonstrates a scalable and safe process for resource upcycling and green hydrogen production for a sustainable energy future.
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http://dx.doi.org/10.1038/s41467-021-22250-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012647PMC
March 2021

Stability and Structure of Bat Major Histocompatibility Complex Class I with Heterologous β2-Microglobulin.

J Vis Exp 2021 03 10(169). Epub 2021 Mar 10.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University; NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention;

The major histocompatibility complex (MHC) plays a pivotal role in antigen peptide presentation and T cell immune responses against infectious disease and tumor development. The hybrid MHC I complexed with heterologous β2-microglobulin (β2m) substitution from different species can be stabilized in vitro. This is a feasible means to study MHC I of mammals, when the homologous β2m is not available. Meanwhile, it is indicated that mammalian β2m substitution does not significantly affect peptide presentation. However, there is limited summarization regarding the methodology and the technology for the hybrid MHC I complexed with heterologous β2-microglobulin (β2m). Herein, methods to evaluate the feasibility of heterologous β2m substitution in MHC I study are presented. These methods include preparation of expression constructs; purification of inclusion bodies and refolding of the MHC complex; determination of protein thermostability; crystal screening and structure determination. This study provides a recommendation for understanding function and structure of MHC I, and is also significant for T cell response evaluation during infectious disease and tumor immunotherapy.
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http://dx.doi.org/10.3791/61462DOI Listing
March 2021

Effect of Roasting on the Antioxidant Activity, Phenolic Composition, and Nutritional Quality of Pumpkin ( L.) Seeds.

Front Nutr 2021 10;8:647354. Epub 2021 Mar 10.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China.

In recent years, with the increasing awareness of health concerns and environment protection needs, there is a growing interest for consumers to choose plant-based food diets compared with those made from animal origin. Pumpkin seed is an excellent dietary source for protein, oil, and some essential micronutrients. Raw pumpkin seed may have a compromised flavor, color, as well as digestibility. Therefore, the objective of present study is to study the influence of roasting (120, 160, and 200°C for 10 min) on the phenolics content, flavonoids content, antioxidant property, fatty acids, and volatile matter composition, as well as protein profile of pumpkin seeds. Our results indicated that, total phenolic compounds, total flavonoids content, as a consequence, total antioxidant capacity increased as the roasting temperature increased. Maillard reaction products and lipid peroxidation products were identified, especially from those pumpkin seeds roasted at high temperature. In the meantime, the composition and content of fatty acids did not change significantly after roasting. The results of electrophoresis and particle size analysis showed that the optimum roasting temperature was 160°C to obtain protein with better nutritional quality. The findings of this study may contribute to the utilization of pumpkin seed component in plant-based diets with increased nutritional quality.
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http://dx.doi.org/10.3389/fnut.2021.647354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988230PMC
March 2021

SARS-CoV-2 infection aggravates chronic comorbidities of cardiovascular diseases and diabetes in mice.

Animal Model Exp Med 2021 03 6;4(1):2-15. Epub 2021 Mar 6.

Key Laboratory of Human Disease Comparative Medicine National Health Commission of China (NHC) Institute of Laboratory Animal Science Peking Union Medicine College Chinese Academy of Medical Sciences Beijing China.

Background: Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID-19. However, how SARS-CoV-2 alters the progression of chronic diseases remain unclear.

Methods: We used adenovirus to deliver h-ACE2 to lung to enable SARS-CoV-2 infection in mice. SARS-CoV-2's impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis.

Results: Pre-existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS-CoV-2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with impaired PI3K/AKT/mTOR signaling.

Conclusion: We established mouse models mimicked the complex pathological symptoms of COVID-19 patients with chronic diseases. Pre-existing diseases could impair the inflammatory responses to SARS-CoV-2 infection, which further aggravated the pre-existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/ame2.12155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954823PMC
March 2021

Thermal hydrolyzed food waste liquor as liquid organic fertilizer.

Sci Total Environ 2021 Jun 12;775:145786. Epub 2021 Feb 12.

Advanced Environmental Biotechnology Centre, Nanyang Environment and Water Research Institute, Nanyang Technological University, Singapore 637141, Singapore; School of Civil and Environmental Engineering, Nanyang Technological University, Singapore 639798, Singapore. Electronic address:

Thermal hydrolysis (TH) is an efficient technology for food waste (FW) management. This study investigated the nutrients released from FW under various TH temperature (140, 160, 180, 200 and 220 °C) and evaluated the feasibility of the hydrolyzed liquor (HL) as liquid organic fertilizer. The phytotoxicity and biotoxicity of HL was analyzed using wheat seed and Pseudomonas putida. Results revealed that TH could effectively solubilize FW and release nutrients (N, P and K) and organic substances. The highest content of total nitrogen (TN, 1685 mgN/L) and phosphorus (TP, 235 mgP/L) in the HL was obtained under 180 °C. The K was 278-293 mg/L regardless of treatment temperature. Secondary nutrients (Ca and Mg) and micro metals (Fe, Cu, Zn, Al, Co and Mn) were all detected at relatively high level, while heavy metals (As and Cd) were generally lower than 0.5 mg/L. Twenty types of free amino acid were identified and the maximum total concentration was 4965.13 mg/L. 2% HL displayed higher germination index (>80%) and enhanced root and shoot lengths. No biotoxicity was observed as confirmed by the bioassay. This study proposes a feasible method to solubilize food waste and produce liquid organic fertilizer.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145786DOI Listing
June 2021

Inhibition of PDE1-B by Vinpocetine Regulates Microglial Exosomes and Polarization Through Enhancing Autophagic Flux for Neuroprotection Against Ischemic Stroke.

Front Cell Dev Biol 2020 4;8:616590. Epub 2021 Feb 4.

Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Exosomes contribute to cell-cell communications. Emerging evidence has shown that microglial exosomes may play crucial role in regulation of neuronal functions under ischemic conditions. However, the underlying mechanisms of microglia-derived exosome biosynthesis are largely unknown. Herein, we reported that the microglial PDE1-B expression was progressively elevated in the peri-infarct region after focal middle cerebral artery occlusion. By an oxygen-glucose-deprivation (OGD) ischemic model in cells, we found that inhibition of PDE1-B by vinpocetine in the microglial cells promoted M2 and inhibited M1 phenotype. In addition, knockdown or inhibition of PDE1-B significantly enhanced the autophagic flux in BV2 cells, and vinpocetine-mediated suppression of M1 phenotype was dependent on autophagy in ischemic conditions. Co-culture of BV2 cells and neurons revealed that vinpocetine-treated BV2 cells alleviated OGD-induced neuronal damage, and treatment of BV2 cells with 3-MA abolished the observed effects of vinpocetine. We further demonstrated that ischemia and vinpocetine treatment significantly altered microglial exosome biogenesis and release, which could be taken up by recipient neurons and regulated neuronal damage. Finally, we showed that the isolated exosome from conditioned BV2 cells is sufficient to regulate cortical neuronal survival . Taken together, these results revealed a novel microglia-neuron interaction mediated by microglia-derived exosomes under ischemic conditions. Our findings further suggest that PDE1-B regulates autophagic flux and exosome biogenesis in microglia which plays a crucial role in neuronal survival under cerebral ischemic conditions.
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http://dx.doi.org/10.3389/fcell.2020.616590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889976PMC
February 2021

Evaluation of cesarean delivery rates in different levels of hospitals in Jiangsu Province, China, using the 10-Group classification system.

J Matern Fetal Neonatal Med 2021 Feb 15:1-7. Epub 2021 Feb 15.

Department of Obstetrics and Gynecology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China.

Objective: To compare cesarean delivery (CD) rates in referral and non-referral hospitals in Maternal Safety Collaboration in Jiangsu province, China.

Methods: Sixteen participants (4 referral hospitals, 12 non-referral hospitals) from Drum Tower Hospital Collaboration for Maternal Safety reported CD rates in 2019 using ten-group classification system and maternal/neonatal morbidity and mortality.

Results: A total of 22,676 CDs were performed among 52,499 deliveries and the average CD rate was 43.2% (range 34.8-69.6%). CD rate in non-referral hospitals (44.7%) was significantly higher than it was in referral hospitals (40.4%,  < .001). Term singleton cephalic nulliparous women with spontaneous labor (Group 1) or induced labor (Group 2a) had higher CD rates if they were cared in non-referral hospitals compared with those in referral hospitals (Group 1: 11.8% vs. 4.4%,  < .001; Group 2a: 29.1% vs. 21.3%,  < .001). In non-referral hospitals, CD rate in Group 5 and the proportion of Group 5 to the overall population were also significantly higher than those in referral hospitals (98.5% vs. 92.5%,  < .001; and 21.0% vs. 14.5%,  < .001).

Conclusion: To decrease the CD rate, we need to take efforts in decreasing unnecessary operations for term singleton cephalic nulliparous women and increasing the rate of trial of labor after CD.
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http://dx.doi.org/10.1080/14767058.2021.1887124DOI Listing
February 2021

Tough and biodegradable polyurethane-curcumin composited hydrogel with antioxidant, antibacterial and antitumor properties.

Mater Sci Eng C Mater Biol Appl 2021 Feb 24;121:111820. Epub 2020 Dec 24.

College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China.

The functionalization of tough and biodegradable hydrogels is an important way to broaden their applications in biomedical field. However, most of the hydrophobic functional drugs are difficult to incorporate with the hydrogels. In this work, curcumin (Cur), a hydrophobic functional drug, was chosen to composite with polyurethane (PU) to obtain PU-Cur hydrogels by a direct and simple in-situ copolymerization. The incorporation of curcumin in PU hydrogel increases the crosslink but reduces the hydrophilicity and degradation rate of PU-Cur hydrogels. Thus, it can increase the mechanical strength to a maximum of 6.4±0.8 MPa and initial modulus to a maximum of 3.0±0.4 MPa. More importantly, curcumin incorporated in PU networks is not deactivated. The degradation products of PU-Curs at relatively low concentrations (2.5 mg/mL) can scavenge free radicals very efficiently (maximum over 90%), which exhibits strong antioxidant properties to improve wound healing. Moreover, based on the photochemical activity of curcumin, notable inhibition effects of the degradation products of PU-Curs against bacteria (maximum over 80%) and cancer cells are demonstrated with blue light treatment as a photodynamic therapy (PDT). Therefore, the beneficial effects of curcumin are retained in PU-Cur hydrogels, suggesting potential use as wound dressings or tumor isolation membranes. This work proposes a promising strategy to combine hydrophobic functional drugs with hydrophilic hydrogels for applications in a wide range of biomaterials.
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http://dx.doi.org/10.1016/j.msec.2020.111820DOI Listing
February 2021

Combined therapy of intensive statin plus intravenous rt-PA in acute ischemic stroke: the INSPIRE randomized clinical trial.

J Neurol 2021 Jul 8;268(7):2560-2569. Epub 2021 Feb 8.

Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, China.

Objective: To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy.

Methods: A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days.

Results: The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran-Mantel-Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999).

Conclusion: The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile.

Clinical Trial Registration: URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642.
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http://dx.doi.org/10.1007/s00415-020-10388-3DOI Listing
July 2021

Electro-acupuncture Protects diabetic nephropathy-induced inflammation through suppression of NLRP3 inflammasome in Renal macrophage isolation.

Endocr Metab Immune Disord Drug Targets 2021 Jan 18. Epub 2021 Jan 18.

Department of Accupuncture, Zibo integrated traditional Chinese and Western Medicine Hospital, Tianjin 300381. China.

Background: With the increasing prevalence of diabetes in recent years, diabetic nephropathy (DN) has also become a dangerous disease that greatly endangers human health. The study was designed to determine the mechanism and effect of Electro-acupuncture (EA) in alleviating DN-induced inflammation.

Methods: Mice were intraperitoneally injected with STZ (streptozotocin, 50 mg/kg, S0130, Sigma, St. Louis, MO, USA) for five consecutive days. After 12 weeks after induction, blood glucose levels were measured (>300 mg/dL).

Results: The serum levels of IL-1β and IL-6 were decreased in EA-treated DN mice, and EA protected renal injury. EA could suppress HMGB1/NLRP3/NF-κB pathway. HMGB1 inhibition increased the anti-inflammatory effects of EA on DN by suppressing NLRP3/NF-κB pathway. The activation of HMGB1 attenuated the anti-inflammatory effects of EA on DN by inducing NLRP3/NF-κB pathway.

Conclusions: These results suggested that EA protected DN-induced inflammation through suppression of NLRP3 inflammasome.
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http://dx.doi.org/10.2174/1871530321666210118161721DOI Listing
January 2021

The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity.

EMBO Rep 2021 02 4;22(2):e51162. Epub 2021 Jan 4.

Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage-associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T-cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.
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http://dx.doi.org/10.15252/embr.202051162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857436PMC
February 2021

Manganese nanodepot augments host immune response against coronavirus.

Nano Res 2020 Dec 29:1-13. Epub 2020 Dec 29.

Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, 100191 China.

Interferon (IFN) responses are central to host defense against coronavirus and other virus infections. Manganese (Mn) is capable of inducing IFN production, but its applications are limited by nonspecific distributions and neurotoxicity. Here, we exploit chemical engineering strategy to fabricate a nanodepot of manganese (nanoMn) based on Mn+. Compared with free Mn, nanoMn enhances cellular uptake and persistent release of Mn in a pH-sensitive manner, thus strengthening IFN response and eliciting broad-spectrum antiviral effects and Preferentially phagocytosed by macrophages, nanoMn promotes M1 macrophage polarization and recruits monocytes into inflammatory foci, eventually augmenting antiviral immunity and ameliorating coronavirus-induced tissue damage. Besides, nanoMn can also potentiate the development of virus-specific memory T cells and host adaptive immunity through facilitating antigen presentation, suggesting its potential as a vaccine adjuvant. Pharmacokinetic and safety evaluations uncover that nanoMn treatment hardly induces neuroinflammation through limiting neuronal accumulation of manganese. Therefore, nanoMn offers a simple, safe, and robust nanoparticle-based strategy against coronavirus.

Electronic Supplementary Material: Supplementary material is available for this article at 10.1007/s12274-020-3243-5 and is accessible for authorized users.
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http://dx.doi.org/10.1007/s12274-020-3243-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770383PMC
December 2020