Publications by authors named "Liwen Zhang"

309 Publications

Multi-focus Network to Decode Imaging Phenotype for Overall Survival Prediction of Gastric Cancer Patients.

IEEE J Biomed Health Inform 2021 Jun 8;PP. Epub 2021 Jun 8.

Gastric cancer (GC) is the third leading cause of cancer-associated deaths globally. Accurate risk prediction of the overall survival (OS) for GC patients shows significant prognostic value, which helps identify and classify patients into different risk groups to benefit from personalized treatment. Many methods based on machine learning algorithms have been widely explored to predict the risk of OS accurately. However, the accuracy of risk prediction has been limited and remains a challenge with existing methods. Few studies have proposed a framework and pay attention to the low-level and high-level features separately for the risk prediction of OS based on computed tomography images of GC patients. To achieve high accuracy, we propose a multi-focus fusion convolutional neural network. The network focuses on low-level and high-level features, where a subnet to focus on lower-level features and the other enhanced subnet with lateral connection to focus on higher-level semantic features. Three independent datasets of 640 GC patients are used to assess our method. Our proposed network is evaluated by metrics of the concordance index and hazard ratio. Our network outperforms existing methods with the highest concordance index and hazard ratio in independent validation and test sets. Our results prove that our architecture can unify the separate low-level and high-level features into a single framework, and can be a powerful method for accurate risk prediction of OS.
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http://dx.doi.org/10.1109/JBHI.2021.3087634DOI Listing
June 2021

The impact of IL-10 and CYP3A5 gene polymorphisms on dose-adjusted trough blood tacrolimus concentrations in early post-renal transplant recipients.

Pharmacol Rep 2021 Jun 5. Epub 2021 Jun 5.

Division of Life Sciences and Medicine, Department of Pharmacy, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China.

Background: The strong inter-individual pharmacokinetic variability and the narrow therapeutic window of tacrolimus (TAC) have hampered the clinical application. Gene polymorphisms play an important role in TAC pharmacokinetics. Here, we investigate the influence of genotypes of IL-10, CYP3A5, CYP2C8, and ABCB1 on dose-adjusted trough blood concentrations (the C/D ratio) of TAC to reveal unclear genetic factors that may affect TAC dose requirements for renal transplant recipients.

Methods: Genetic polymorphisms of IL-10, CYP3A5, CYP2C8, and ABCB1 in 188 renal transplant recipients were determined using Kompetitive Allele Specific PCR (KASP). Statistical analysis was applied to examine the effect of genetic variation on the TAC C/D at 5, 10, 15, and 30 days after transplantation.

Results: Recipients carrying the IL-10 -819C > T TT genotype showed a significantly higher TAC C/D than those with the TC/CC genotype (p < 0.05). Additionally, the TAC C/D values of recipients with the capacity for low IL-10 activity (-819 TT) engrafted with CYP3A5 non-expressers were higher compared to the intermediate/high activity of IL-10 -819C > T TC or CC carrying CYP3A5 expressers, and the difference was statistically significant at different time points (p < 0.05).

Conclusions: Genetic polymorphisms of IL-10 -819C > T and CYP3A5 6986A > G influence the TAC C/D, which may contribute to variation in TAC dose requirements during the early post-transplantation period. Detecting IL-10 -819C > T and CYP3A5 6986A > G polymorphisms may allow determination of individualized tacrolimus dosage regimens for renal transplant recipients during the early post-transplantation period.
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http://dx.doi.org/10.1007/s43440-021-00288-2DOI Listing
June 2021

Bayesian phase II clinical trial design with noncompliance.

Stat Med 2021 May 28. Epub 2021 May 28.

School of Statistics and Management, Shanghai University of Finance and Economics, Shanghai, China.

Noncompliance issue is common in early phase clinical trials; and may lead to biased estimation of the intent-to-treat effect and incorrect conclusions for the clinical trial. In this work, we propose a Bayesian approach for sequentially monitoring the phase II randomized clinical trials that takes account for the noncompliance information. We adopt the principal stratification framework and propose to use Bayesian additive regression trees for selecting useful baseline covariates and estimating the complier average causal effect (CACE) for both efficacy and toxicity outcomes. The decision of early termination or not is then made adaptively based on the estimated CACE from the accumulated data. Simulation studies have confirmed the excellent performance of the proposed design in the presence of noncompliance.
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http://dx.doi.org/10.1002/sim.9041DOI Listing
May 2021

Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin.

Hum Mol Genet 2021 May 5. Epub 2021 May 5.

Centre for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, 43205, OH, USA.

ΔR4-R23/ΔCT micro-dystrophin (μDys) is a miniaturized version of dystrophin currently evaluated in a Duchenne muscular dystrophy (DMD) gene therapy trial to treat skeletal and cardiac muscle disease. In pre-clinical studies, μDys efficiently rescues cardiac histopathology, but only partially normalizes cardiac function. To gain insights into factors that may impact the cardiac therapeutic efficacy of μDys, we compared by mass spectrometry the composition of purified dystrophin and μDys protein complexes in the mouse heart. We report that compared to dystrophin, μDys has altered associations with α1- and β2-syntrophins, as well as cavins, a group of caveolae-associated signaling proteins. In particular, we found that membrane localization of cavins -1 and - 4 in cardiomyocytes requires dystrophin and is profoundly disrupted in the heart of mdx5cv mice, a model of DMD. Following cardiac stress/damage, membrane-associated cavin-4 recruits the signaling molecule ERK to caveolae, which activates key cardio-protective responses. Evaluation of ERK signaling revealed a profound inhibition, below physiological baseline, in the mdx5cv mouse heart. Expression of μDys in mdx5cv mice prevented the development of cardiac histopathology but did not rescue membrane localization of cavins nor did it normalize ERK signaling. Our study provides the first comparative analysis of purified protein complexes assembled in vivo by full-length dystrophin and a therapeutic micro-dystrophin construct. This has revealed disruptions in cavins and ERK signaling that may contribute to DMD cardiomyopathy. This new knowledge is important for ongoing efforts to prevent and treat heart disease in DMD patients.
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http://dx.doi.org/10.1093/hmg/ddab133DOI Listing
May 2021

An electrically switchable anti-ferroelectric bilayer InSe based opto-spintronic device.

Nanoscale 2021 May 29;13(18):8555-8561. Epub 2021 Apr 29.

State Key Laboratory of Quantum Optics and Quantum Optics Devices, Institute of Laser Spectroscopy, Shanxi University, Taiyuan 030006, China.

Based on non-equilibrium Green's function combined with density functional theory (NEGF-DFT), we theoretically investigate the spin-related photogalvanic effect (PGE) in two anti-ferroelectric bilayer InSe structures by atomic first-principles calculations. It is found that, due to the absence of inversion symmetry and the presence of strong spin-orbital interaction (SOI) in anti-ferroelectric bilayer InSe, the photoinduced charge-to-spin conversion can be achieved via the PGE. The generated spin-dependent photocurrent is largely spin-polarized and the corresponding spin polarization can vary from 0% to 100% depending on the photon energies, polarization and incident angles. Furthermore, it is found that, by tuning the polarization and the incident angles of light, the fully spin-polarized and pure spin photocurrent can be obtained. Most importantly, the spin dependent photocurrent can be largely tuned through the transition between two anti-ferroelectric bilayer InSe states by the gate voltage. The defined relative spin dependent photoresponse change ratio n between two states is extremely large and its maximum value can be in the order of ∼10. Therefore, our work demonstrates the great potential of bilayer InSe's novel application in two-dimensional non-volatile opto-spintronic devices.
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http://dx.doi.org/10.1039/d1nr00369kDOI Listing
May 2021

Prognostic and Diagnostic Values of Circulating Tumor Cells and Tumor Markers for Lung Cancer.

Clin Lab 2021 Apr;67(4)

Background: Circulating tumor cells (CTCs) and tumor markers (TMs) are two kinds of diagnostic and prognostic markers for lung cancer. CTCs detect tumor cells, while TMs detect molecules in peripheral blood. This study aimed to investigate which marker is a better choice for the diagnosis and prognostication of lung cancer.

Methods: The diagnostic values were compared by generating receiver operating characteristic (ROC) curves and performing logistic regression analyses. The prognostic values were compared by generating Kaplan-Meier curves of CTCs, TMs, and clinical characteristics.

Results: The ROC curve analysis showed that CEA had the highest AUC (area under curve) among the TMs, while CTCs had a higher AUC than any of the TMs. Logistic regression analysis indicated that gender, smoking status, CTCs, and CA15-3 were involved in lung cancer prediction. The Kaplan-Meier curves showed that smoking status, pleural invasion, lymph node infiltration, and stage I - II disease were related to poor prognosis. Patients with CTCs or CA125 positivity also had a poor prognosis.

Conclusions: Our data indicate that CTCs are a better choice than TMs for the diagnosis and prognostication of lung cancer.
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http://dx.doi.org/10.7754/Clin.Lab.2020.200654DOI Listing
April 2021

Gene expression profiling of early Parkinson's disease patient reveals redox homeostasis.

Neurosci Lett 2021 05 12;753:135893. Epub 2021 Apr 12.

Neurotoxin Research Center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, PR China. Electronic address:

Parkinson's disease (PD) is slowly progressive. Due to the lack of specific and sensitive biomarkers, the majority of PD patients are in the advanced stages when diagnosed. This study aimed to investigate biomarkers for early PD diagnosis. We first selected differential mRNAs by analysis of a Gene Expression Omnibus (GEO) data set. Next, we performed RNA sequencing to select differential mRNAs. After an integrated analysis of GEO and RNAseq data, we identified the PD early diagnosis biomarkers associated with oxidative stress. By function analysis, cellular response to hormone stimulus and response to the oxygen-containing compound was involved in the top Gene Set Enrichment Analysis (GSEA)s of the two cohorts. Moreover, SOCS7 was included in these GSEAs coincidentally. Further, by analyzing SOCS7 and its physical interactors, we found they mainly participate in immunity and redox homeostasis related processes, which might play a significant role in PD. Thus, our results suggest SOCS7 might be the potential diagnostic marker for PD.
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http://dx.doi.org/10.1016/j.neulet.2021.135893DOI Listing
May 2021

Utility of Preoperative Inflammatory Markers to Distinguish Epithelial Ovarian Cancer from Benign Ovarian Masses.

J Cancer 2021 5;12(9):2687-2693. Epub 2021 Mar 5.

Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Inflammatory markers have been reported to be predictors for the presence of epithelial ovarian cancer (EOC), however, the cut-off value of each marker remains unclear and predictive capability of the markers in different histology types of EOC is still unknown. A total of 207 patients with benign ovarian masses and 887 EOC patients who underwent surgical resection, and were pathologically diagnosed were included. We compared the difference of preoperative inflammatory markers between benign ovarian masses and EOC patients. Stratified analysis by histology subtype was further conducted. Logistic regression analyses and receiver operating characteristic (ROC) curves was used to evaluate the predictive capability of the markers. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were significantly associated with all stages and subtypes of EOC (P<0.001). The optimal cut-off points based on ROC curve analyses for NLR, PLR, and LMR were found to be 2.139 (AUC=0.749, <0.001), 182.698 (AUC=0.730, <0.001), and 3.619 (AUC = 0.709, <0.001), respectively. In low CA125 level patients, high level of NLR and PLR increase the risk of endometrioid EOC, while low level of LMR were significantly associated with an increased risk of serous EOC. In addition to CA125, NLR, PLR, and LMR could be used as predictors of EOC and preoperative inflammatory markers may be used as a potential biomarker for predicting different histotypes of EOC.
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http://dx.doi.org/10.7150/jca.51642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040725PMC
March 2021

Gradient Heating Effect Modulated by Hydrophobic/Hydrophilic Carbon Nanotube Network Structures for Ultrafast Solar Steam Generation.

ACS Appl Mater Interfaces 2021 Apr 14;13(16):19109-19116. Epub 2021 Apr 14.

School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230000, China.

The emerging interface solar-thermal water evaporation has been widely studied to solve fresh water shortage because of its high solar-thermal conversion efficiency, environmental friendliness, and low cost. However, traditional water evaporation systems inevitably lose heat to the environment, which not only greatly affects the water evaporation rate but also hinders their practical applications. In this work, an interface solar-thermal water evaporation system with enhanced heat localization, which is combined by a hydrophobic carbon nanotube (CNT) film (heating layer) and hydrophilic polyvinyl alcohol (PVA)/CNT foam (evaporating layer), is demonstrated. Under solar irradiation, the temperature of the hydrophobic CNT film is higher than that of the hydrophilic PVA/CNT foam due to the differences in wettability, so the thermal energy in the CNT film can be continuously transferred to the PVA/CNT foam evaporator, forming a gradient heating effect and greatly increasing the water evaporation rate. As a result, the water evaporation rate can reach 4.2 kg m h under a solar illumination of 1 kW m, which is among the highest water evaporation rate levels. More importantly, this water evaporation system structure is simple, can be easily scaled up, and has gradient applicability to other photothermal materials, which provides a route to improve the interfacial solar steam evaporation rate.
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http://dx.doi.org/10.1021/acsami.0c21831DOI Listing
April 2021

Bicarbonate ion transport by the electrogenic Na /HCO cotransporter, NBCe1, is required for normal electrical slow-wave activity in mouse small intestine.

Neurogastroenterol Motil 2021 Apr 10:e14149. Epub 2021 Apr 10.

Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA.

Background: Normal gastrointestinal motility depends on electrical slow-wave activity generated by interstitial cells of Cajal (ICC) in the tunica muscularis of the gastrointestinal tract. A requirement for HCO in extracellular solutions used to record slow waves indicates a role for HCO transport in ICC pacemaking. The Slc4a4 gene transcript encoding the electrogenic Na /HCO cotransporter, NBCe1, is enriched in mouse small intestinal myenteric region ICC (ICC-MY) that generate slow waves. This study aimed to determine how extracellular HCO concentrations affect electrical activity in mouse small intestine and to determine the contribution of NBCe1 activity to these effects.

Methods: Immunohistochemistry and sharp electrode electrical recordings were used.

Key Results: The NBCe1 immunoreactivity was localized to ICC-MY of the tunica muscularis. In sharp electrode electrical recordings, removal of HCO from extracellular solutions caused significant, reversible, depolarization of the smooth muscle and a reduction in slow-wave amplitude and frequency. In 100 mM HCO , the muscle hyperpolarized and slow wave amplitude and frequency increased. The effects of replacing extracellular Na with Li , an ion that does not support NBCe1 activity, were similar to, but larger than, the effects of removing HCO . There were no additional changes to electrical activity when HCO was removed from Li containing solutions. The Na /HCO cotransport inhibitor, S-0859 (30µM) significantly reduced the effect of removing HCO on electrical activity.

Conclusions & Inferences: These studies demonstrate a major role for Na /HCO cotransport by NBCe1 in electrical activity of mouse small intestine and indicated that regulation of intracellular acid:base homeostasis contributes to generation of normal pacemaker activity in the gastrointestinal tract.
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http://dx.doi.org/10.1111/nmo.14149DOI Listing
April 2021

Quantitative detection of circulating MT-ND1 as a potential biomarker for colorectal cancer.

Bosn J Basic Med Sci 2021 Mar 15. Epub 2021 Mar 15.

Shanghai National Engineering Research Center for Biochip at Shanghai and Shanghai Biochip Limited Corporation, Shanghai, China.

Liquid biopsy represents a diagnostic and monitoring tool and the circulating cell-free mitochondrial DNA (mtDNA) plays a vital role in tumor diagnosis and dynamic assessment. Colorectal cancer (CRC) is one of the most common fatal cancers worldwide. Mitochondrially encoded NADH dehydrogenase subunit 1 (MT-ND1) encodes the biggest subunit of respiratory complex I of mtDNA, and mutations in the MT-ND1 are common in CRC. We sought to determine if mutations in circulating MT-ND1 could be a potential biomarker for colorectal cancer. In this study, twenty-two CRC patients at Zhujiang Hospital were included. We mainly used droplet digital PCR to determine the mutation status of MT-ND1, combined with clinical data. In the experiment in vivo, cell-free mtDNA generally presented high concordance with tumor tissues. By quantitative PCR, the MT-ND1 content of plasma in CRC patients was significantly higher than that in healthy individuals (58.01 vs. 0.64, p=0.027). The detection of circulating MT-ND1 content and variants (m.3606 A>G, m.3970 C>T, m.4071 C>T, m.4086 C>T) in cfDNA showed a good correlation with predicted tumor response and progression to chemotherapy. In conclusion, the content and variants of circulating MT-ND1 may become a versatile tool for the diagnosis and monitoring of colorectal cancer.
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http://dx.doi.org/10.17305/bjbms.2021.5576DOI Listing
March 2021

PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications.

Nat Cell Biol 2021 Apr 5;23(4):424-436. Epub 2021 Apr 5.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Although high-throughput RNA sequencing (RNA-seq) has greatly advanced small non-coding RNA (sncRNA) discovery, the currently widely used complementary DNA library construction protocol generates biased sequencing results. This is partially due to RNA modifications that interfere with adapter ligation and reverse transcription processes, which prevent the detection of sncRNAs bearing these modifications. Here, we present PANDORA-seq (panoramic RNA display by overcoming RNA modification aborted sequencing), employing a combinatorial enzymatic treatment to remove key RNA modifications that block adapter ligation and reverse transcription. PANDORA-seq identified abundant modified sncRNAs-mostly transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs)-that were previously undetected, exhibiting tissue-specific expression across mouse brain, liver, spleen and sperm, as well as cell-specific expression across embryonic stem cells (ESCs) and HeLa cells. Using PANDORA-seq, we revealed unprecedented landscapes of microRNA, tsRNA and rsRNA dynamics during the generation of induced pluripotent stem cells. Importantly, tsRNAs and rsRNAs that are downregulated during somatic cell reprogramming impact cellular translation in ESCs, suggesting a role in lineage differentiation.
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http://dx.doi.org/10.1038/s41556-021-00652-7DOI Listing
April 2021

Creatine promotes cancer metastasis through activation of Smad2/3.

Cell Metab 2021 Jun 2;33(6):1111-1123.e4. Epub 2021 Apr 2.

Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China. Electronic address:

As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.
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http://dx.doi.org/10.1016/j.cmet.2021.03.009DOI Listing
June 2021

Integrating No.3 lymph nodes and primary tumor radiomics to predict lymph node metastasis in T1-2 gastric cancer.

BMC Med Imaging 2021 Mar 23;21(1):58. Epub 2021 Mar 23.

Department of Radiology, Affiliated People's Hospital of JiangSu University, Zhenjiang, People's Republic of China.

Background: This study aimed to develope and validate a radiomics nomogram by integrating the quantitative radiomics characteristics of No.3 lymph nodes (LNs) and primary tumors to better predict preoperative lymph node metastasis (LNM) in T1-2 gastric cancer (GC) patients.

Methods: A total of 159 T1-2 GC patients who had undergone surgery with lymphadenectomy between March 2012 and November 2017 were retrospectively collected and divided into a training cohort (n = 80) and a testing cohort (n = 79). Radiomic features were extracted from both tumor region and No. 3 station LNs based on computed tomography (CT) images per patient. Then, key features were selected using minimum redundancy maximum relevance algorithm and fed into two radiomic signatures, respectively. Meanwhile, the predictive performance of clinical risk factors was studied. Finally, a nomogram was built by merging radiomic signatures and clinical risk factors and evaluated by the area under the receiver operator characteristic curve (AUC) as well as decision curve.

Results: Two radiomic signatures, reflecting phenotypes of the tumor and LNs respectively, were significantly associated with LN metastasis. A nomogram incorporating two radiomic signatures and CT-reported LN metastasis status showed good discrimination of LN metastasis in both the training cohort (AUC 0.915; 95% confidence interval [CI] 0.832-0.998) and testing cohort (AUC 0.908; 95% CI 0.814-1.000). The decision curve also indicated its potential clinical usefulness.

Conclusions: The nomogram received favorable predictive accuracy in predicting No.3 LNM in T1-2 GC, and the nomogram showed positive role in predicting LNM in No.4 LNs. The nomogram may be used to predict LNM in T1-2 GC and could assist the choice of therapy.
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http://dx.doi.org/10.1186/s12880-021-00587-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989204PMC
March 2021

A rapid and accurate method for screening T-2 toxin in food and feed using competitive AlphaLISA.

FEMS Microbiol Lett 2021 Apr;368(6)

Anhui Medical University, Hefei, Anhui 230032, China.

T-2 is a common mycotoxin contaminating cereal crops. Chronic consumption of food contaminated with T-2 toxin can lead to death, so simple and accurate detection methods in food and feed are necessary. In this paper, we establish a highly sensitive and accurate method for detecting T-2 toxin using AlphaLISA. The system consists of acceptor beads labeled with T-2-bovine serum albumin (BSA), streptavidin-labeled donor beads and biotinylated T-2 antibodies. T-2 in the sample matrix competes with T-2-BSA for antibodies. Adding biotinylated antibodies to the test well followed by T-2 and T-2-BSA acceptor beads yielded a detection range of 0.03-500 ng/mL. The half-maximal inhibitory concentration was 2.28 ng/mL and the coefficient of variation was <10%. In addition, this method had no cross-reaction with other related mycotoxins. This optimized method for extracting T-2 from food and feed samples achieved a recovery rate of approximately 90% in T-2 concentrations as low as 1 ng/mL, better than the performance of a commercial ELISA kit. This competitive AlphaLISA method offers high sensitivity, good specificity, good repeatability and simple operation for detecting T-2 toxin in food and feed.
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http://dx.doi.org/10.1093/femsle/fnab029DOI Listing
April 2021

CD146 is a Novel ANGPTL2 Receptor that Promotes Obesity by Manipulating Lipid Metabolism and Energy Expenditure.

Adv Sci (Weinh) 2021 Mar 27;8(6):2004032. Epub 2021 Jan 27.

Key Laboratory of RNA Biology Key Laboratory of Protein and Peptide Pharmaceuticals Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China.

Obesity and its related complications pose an increasing threat to human health; however, targetable obesity-related membrane receptors are not yet elucidated. Here, the membrane receptor CD146 is demonstrated to play an essential role in obesity. In particular, CD146 acts as a new adipose receptor for angiopoietin-like protein 2 (ANGPTL2), which is thought to act on endothelial cells to activate adipose inflammation. ANGPTL2 binds to CD146 to activate cAMP response element-binding protein (CREB), which then upregulates CD146 during adipogenesis and adipose inflammation. CD146 is present in preadipocytes and mature adipocytes, where it is mediated by its ligands ANGPTL2 and galectin-1. In preadipocytes, CD146 ablation suppresses adipogenesis, whereas the loss of CD146 in mature adipocytes suppresses lipid accumulation and enhances energy expenditure. Moreover, anti-CD146 antibodies inhibit obesity by disrupting the interactions between CD146 and its ligands. Together, these findings demonstrate that ANGPTL2 directly affects adipocytes via CD146 to promote obesity, suggesting that CD146 can be a potential target for treating obesity.
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http://dx.doi.org/10.1002/advs.202004032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967059PMC
March 2021

Length-dependent carbon nanotube film structures and mechanical properties.

Nanotechnology 2021 Apr 6;32(26). Epub 2021 Apr 6.

Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27695, United States of America.

We investigated the microstructures of carbon nanotube (CNT) films and the effect of CNT length on their mechanical performance. 230 μm-, 300 μm-, and 360 μm- long CNTs were grown and used to fabricate CNT films by a winding process. Opposite from the length effect on CNT fibers, it has been found that the mechanical properties of the CNT films decrease with increasing CNT length. Without fiber twisting, short CNTs tend to bundle together tightly by themselves in the film structure, resulting in an enhanced packing density; meanwhile, they also provide a high degree of CNT alignment, which prominently contributes to high mechanical properties of the CNT films. When CNTs are long, they tend to be bent and entangled, which significantly reduce their packing density, impairing the film mechanical behaviors severely. It has also been unveiled that the determinant effect of the CNT alignment on the film mechanical properties is more significant than that of the film packing density. These findings provide guidance on the optimal CNT length when attempting to fabricate high-performance macroscopic CNT assemblies.
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http://dx.doi.org/10.1088/1361-6528/abef92DOI Listing
April 2021

SNPs within microRNA binding sites and the prognosis of breast cancer.

Aging (Albany NY) 2021 02 26;13(5):7465-7480. Epub 2021 Feb 26.

Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China.

Single nucleotide polymorphisms (SNPs) within microRNA binding sites can affect the binding of microRNA to mRNA and regulate gene expression, thereby contributing to cancer prognosis. Here we performed a two-stage study of 2647 breast cancer patients to explore the association between SNPs within microRNA binding sites and breast cancer prognosis. In stage I, we genotyped 192 SNPs within microRNA binding sites using the Illumina Goldengate platform. In stage II, we validated SNPs associated with breast cancer prognosis in another dataset using the TaqMan platform. We identified 8 SNPs significantly associated with breast cancer prognosis in stage I (<0.05), and only rs10878441 was statistically significant in stage II (AA vs CC, HR=2.21, 95% CI: 1.11-4.42, =0.024). We combined the data from stage I and stage II, and found that, compared with rs10878441 AA genotype, CC genotype was associated with poor survival of breast cancer (HR=2.19, 95% CI: 1.30-3.70, =0.003). Stratified analyses demonstrated that rs10878441 was related to breast cancer prognosis in grade II and lymph node-negative patients (<0.05). The Leucine-rich repeat kinase 2 (LRRK2) rs10878441 CC genotype is associated with poor prognosis of breast cancer in a Chinese population and may be used as a potential prognostic biomarker for breast cancer. • The LRRK2 rs10878441 CC genotype is associated with poor prognosis of breast cancer in a Chinese population. • Stratified analyses demonstrated that rs10878441 was related to breast cancer prognosis in grade II patients and lymph node-negative patients.
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http://dx.doi.org/10.18632/aging.202612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993692PMC
February 2021

Cooperation-based sperm clusters mediate sperm oviduct entry and fertilization.

Protein Cell 2021 Mar 1. Epub 2021 Mar 1.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1007/s13238-021-00825-yDOI Listing
March 2021

Long-term exposure to ambient PM and stroke mortality among urban residents in northern China.

Ecotoxicol Environ Saf 2021 Apr 24;213:112063. Epub 2021 Feb 24.

Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin 300070, China; Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin 300070, China. Electronic address:

Evidence is still limited for the role of long-term PM exposure in cerebrovascular diseases among residents in high pollution regions. The study is aimed to investigate the long-term effects of PM exposure on stroke mortality, and further explore the effect modification of temperature variation on the PM-mortality association in northern China. Based on a cohort data with an average follow-up of 9.8 years among 38,435 urban adults, high-resolution estimates of PM derived from a satellite-based model were assigned to each participant. A Cox regression model with time-varying exposures and strata of geographic regions was employed to assess the risks of stroke mortality associated with PM, after adjusting for individual risk factors. The cross-product term of PM exposure and annual temperature range was further added into the regression model to test whether the long-term temperature variation would modify the association of PM with stroke mortality. Among the study participants, the annual mean level of PM concentration was 66.3 μg/m ranging from 39.0 μg/m to 100.6 μg/m. For each 10 μg/m increment in PM, the hazard ratio (HR) was 1.31 (95% CI: 1.04-1.65) for stroke mortality after multivariable adjustment. In addition, the HRs of PM decreased gradually as the increase of annual temperature range with the HRs of 1.95 (95% CI: 1.36-2.81), 1.53 (95% CI: 1.06-2.22), and 1.11 (95% CI: 0.75-1.63) in the low, middle, and high group of annual temperature range, respectively. The findings provided further evidence of long-term PM exposure on stroke mortality in high-exposure settings such as northern China, and also highlighted the view that assessing the adverse health effects of air pollution might not ignore the role of temperature variations in the context of climate change.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150861PMC
April 2021

N-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles.

Dev Cell 2021 Mar 19;56(5):702-715.e8. Epub 2021 Feb 19.

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China. Electronic address:

N6-methyladenosine (mA), one of the most prevalent RNA post-transcriptional modifications, is involved in numerous biological processes. In previous studies, the functions of mA were typically identified by perturbing the activity of the methyltransferase complex. Here, we dissect the contribution of mA to an individual-long noncoding RNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The mutant MALAT1 lacking mA-motifs significantly suppressed the metastatic potential of cancer cells both in vitro and in vivo in mouse. Super-resolution imaging showed that the concatenated mA residues on MALAT1 acted as a scaffold for recruiting YTH-domain-containing protein 1 (YTHDC1) to nuclear speckles. We further reveal that the recognition of MALAT1-mA by YTHDC1 played a critical role in maintaining the composition and genomic binding sites of nuclear speckles, which regulate the expression of several key oncogenes. Furthermore, artificially tethering YTHDC1 onto mA-deficient MALAT1 largely rescues the metastatic potential of cancer cells.
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http://dx.doi.org/10.1016/j.devcel.2021.01.015DOI Listing
March 2021

Salivary microbiome and periodontal status of patients with periodontitis during the initial stage of orthodontic treatment.

Am J Orthod Dentofacial Orthop 2021 May 16;159(5):644-652. Epub 2021 Feb 16.

Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China. Electronic address:

Introduction: Patients with severe periodontitis typically present with pathologic tooth migration. To improve esthetics and masticatory function, orthodontic treatment is required. Research on periodontal orthodontic treatment has been sparse, particularly from the microbial perspective. Hence, we analyzed the microbial and clinical changes in patients with well-controlled periodontitis in the early stage of orthodontic treatment.

Methods: Ten patients with well-controlled periodontitis were asked to collect saliva before and 1 and 3 months after appliance placement (T0, T1, and T2, respectively) and underwent clinical examinations before and 1, 3, and 6 months after appliance placement (T0, T1, T2, and T3, respectively). The microbial community of saliva was analyzed by 16S rRNA gene sequencing. Gingival index, the plaque index, and the probing pocket depth were clinically assessed.

Results: The plaque index significantly increased from T0 to T1 and decreased at T2 and T3. The probing pocket depth and gingival index increased slightly at T2, but not significantly, in both the high-risk site and low-risk site. The alpha and beta diversity increased at T1. The microbial community structure was similar at T0 and T2. The relative abundance of core genera and periodontal pathogens was stable during the initial 3 months of orthodontic treatment.

Conclusions: The orthodontic appliance promoted plaque accumulation and altered the microbial community of patients with well-controlled periodontitis during the first month of orthodontic treatment. The microbial community returned to the basal composition at 3 months after appliance placement, and the periodontal inflammation during the 6-months orthodontic treatment was under control.
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http://dx.doi.org/10.1016/j.ajodo.2019.11.026DOI Listing
May 2021

Clinical characteristics of hospitalized mild/moderate COVID-19 patients with a prolonged negative conversion time of SARS-CoV-2 nucleic acid detection.

BMC Infect Dis 2021 Feb 3;21(1):141. Epub 2021 Feb 3.

Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China.

Background: The impact of COVID-19 has been devastating on a global scale. The negative conversion time (NCT) of SARS-CoV-2 RNA is closely related to clinical manifestation and disease progression in COVID-19 patients. Our study aimed to predict factors associated with prolonged NCT of SARS-CoV-2 RNA in mild/moderate COVID-19 patients.

Methods: The clinical features, laboratory data and treatment outcomes of COVID-19 patients were retrospectively analyzed. Then univariate and multivariate analysis were used to screen out risk factors of influencing prolonged NCT of SARS-CoV-2 RNA.

Results: Thirty-two hospitalized mild/moderate COVID-19 patients were enrolled. The general clinical symptoms were cough (78.1%), fever (75%), diarrhea (68.8%), expectoration (56.3%), and nausea (37.5%). More than 40% of the patients had decreased erythrocyte, hemoglobin and leucocyte and 93.8% patients were detected in abnormalities of chest CT. The median NCT of SARS-CoV-2 RNA was 19.5 days (IQR: 14.25-25). Univariate analysis found fever, nausea, diarrhea and abnormalities in chest CTs were positively associated with prolonged NCT of viral RNA (P< 0.05). The multivariate Cox proportional hazard model revealed that fever [Exp (B), 0.284; 95% CI, 0.114-0.707; P<0.05] and nausea [Exp (B), 0.257; 95%CI, 0.096-0.689; P<0.05] were two significant independent factors.

Conclusions: Fever and nausea were two significant independent factors in prolonged NCT of viral RNA in mild/moderate COVID-19 patients, which provided a useful references for disease progression and treatment of COVID-19.
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http://dx.doi.org/10.1186/s12879-021-05851-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856599PMC
February 2021

lncRNA-Xist/miR-101-3p/KLF6/C/EBPα axis promotes TAM polarization to regulate cancer cell proliferation and migration.

Mol Ther Nucleic Acids 2021 Mar 10;23:536-551. Epub 2020 Dec 10.

Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang City, 110122 Liaoning Province, China.

The phenotypic switch in tumor-associated macrophages (TAMs) mediates immunity escape of cancer. However, the underlying mechanisms in the TAM phenotypic switch have not been systematically elucidated. In this study, long noncoding RNA (lncRNA)-Xist, CCAAT/enhancer-binding protein (C/EBP)α, and Kruppel-like factor 6 (KLF6) were upregulated, whereas microRNA (miR)-101 was downregulated in M1 macrophages-type (M1). Knockdown of Xist or overexpression of miR-101 in M1 could induce M1-to-M2 macrophage-type (M2) conversion to promote cell proliferation and migration of breast and ovarian cancer by inhibiting C/EBPα and KLF6 expression. Furthermore, miR-101 could combine with both Xist and C/EBPα and KLF6 through the same microRNA response element (MRE) predicted by bioinformatics and verified by luciferase reporter assays. Moreover, we found that miR-101 knockdown restored the decreased M1 marker and the increased M2 marker expression and also reversed the promotion of proliferation and migration of human breast cancer cells (MCF-7) and human ovarian cancer (OV) cells caused by silencing Xist. Generally, the present study indicates that Xist could mediate macrophage polarization to affect cell proliferation and migration of breast and ovarian cancer by competing with miR-101 to regulate C/EBPα and KLF6 expression. The promotion of Xist expression in M1 macrophages and inhibition of miR-101 expression in M2 macrophages might play an important role in inhibiting breast and ovarian tumor proliferation and migration abilities.
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http://dx.doi.org/10.1016/j.omtn.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810606PMC
March 2021

Long-term exposure to high particulate matter pollution and incident hypertension: a 12-year cohort study in northern China.

J Hum Hypertens 2021 Jan 18. Epub 2021 Jan 18.

Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin, 300070, China.

Numerous cohort studies have reported the association of long-term exposure to particulate matter <10 μm in diameter (PM) and hypertension in American and European countries. However, these results have been inconsistent and subject to various confounding factors. The study aimed to explore the effect of long-term exposure to high-level concentrations of PM on incident hypertension in a large-scale cohort from northern China. A retrospective cohort study of 39,054 participants aged between 23 and 98 years old from four cities in northern China was followed from 1998 to 2009. Excluding those with hypertension, 37,386 non-hypertensive participants (overall population) were followed for self-reported hypertension. The individuals' exposure to PM was the mean concentration during the follow-up period, according to the data of local environmental monitoring centers. Hazard ratios (HRs) were calculated by Cox proportional hazards models. The adjusted potential confounding factors included sociodemographic information, lifestyle, and diet. There were 2619 (7.0%) incident cases of hypertension among the overall population. In multivariable models, the HR (95% CI) of incident hypertension was 1.537 (1.515, 1.560) for each 10 μg/m increase in PM. Stratified analyses showed individuals (age <65) were prone to developing hypertension. Moreover, the effects of PM increased and produced an HR (95% CI) of 1.555 (1.527, 1.584) for the healthy population in the sensitivity analysis. We found that the association between long-term exposure to PM air pollution and incident hypertension was significantly positive.
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http://dx.doi.org/10.1038/s41371-020-00443-xDOI Listing
January 2021

Roles of oxygen level and hypoxia-inducible factor signaling pathway in cartilage, bone and osteochondral tissue engineering.

Biomed Mater 2021 Feb 18;16(2):022006. Epub 2021 Feb 18.

State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, People's Republic of China.

The repair and treatment of articular cartilage injury is a huge challenge of orthopedics. Currently, most of the clinical methods applied in treating cartilage injuries are mainly to relieve pains rather than to cure them, while the strategy of tissue engineering is highly expected to achieve the successful repair of osteochondral defects. Clear understandings of the physiological structures and mechanical properties of cartilage, bone and osteochondral tissues have been established, but the understanding of their physiological heterogeneity still needs further investigation. Apart from the gradients in the micromorphology and composition of cartilage-to-bone extracellular matrixes, an oxygen gradient also exists in natural osteochondral tissue. The response of hypoxia-inducible factor (HIF)-mediated cells to oxygen would affect the differentiation of stem cells and the maturation of osteochondral tissue. This article reviews the roles of oxygen level and HIF signaling pathway in the development of articular cartilage tissue, and their prospective applications in bone and cartilage tissue engineering. The strategies for regulating HIF signaling pathway and how these strategies finding their potential applications in the regeneration of integrated osteochondral tissue are also discussed.
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http://dx.doi.org/10.1088/1748-605X/abdb73DOI Listing
February 2021

Hierarchical and heterogeneous hydrogel system as a promising strategy for diversified interfacial tissue regeneration.

Biomater Sci 2021 Mar;9(5):1547-1573

State Key Laboratory of Organic-Inorganic Composites; Beijing Laboratory of Biomedical Materials; Beijing University of Chemical Technology, Beijing 100029, P.R. China.

Despite breakthroughs in tissue engineering, a tremendous problem still lies in repairing the interfacial tissue which connects soft tissue to hard tissue, particularly cartilage-bone, tendon/ligament-bone, and cementum-ligament-bone interfaces. The challenge comes from the complicated biophysical and biochemical characteristics of interfacial tissues, involving a graded variation of chemical components, structures, and mechanical properties as well as a heterogeneous cell distribution from the soft end to the hard end. Accordingly, significant progress has been made in the design of hierarchical and heterogeneous hydrogel systems in order to solve this problem. Advanced programmable technologies, such as 3D printing and microfluidic platforms, have shown potential in constructing templates or scaffolds with tissue-specific characteristics. The structural specialty of the three aforementioned interfacial tissues is summarized in this review. Then the text concentrates on how to utilize different scale hydrogels (from chemical variation, nanoscale, microscale to cellular regulation) to fabricate gradient constructions for regenerating interfacial tissues, together with in vitro and in vivo outcomes. In particular, the fabrication of continuous gradients is highlighted in this review. Promisingly, the versatile designs involved in fabricating hierarchical and heterogeneous hydrogel systems are predicted to tackle the unsolved problems, and this interfacial tissue engineering methodology is expected to expand its use in therapeutic applications.
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http://dx.doi.org/10.1039/d0bm01595dDOI Listing
March 2021

Species identification and antimicrobial susceptibility testing of non-tuberculous mycobacteria isolated in Chongqing, Southwest China.

Epidemiol Infect 2020 12 28;149:e7. Epub 2020 Dec 28.

Faculty of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing401331, China.

With the rapid rise in the prevalence of non-tuberculous mycobacteria (NTM) diseases across the world, the microbiological diagnosis of NTM isolates is becoming increasingly important for the diagnosis and treatment of NTM disease. In this study, the clinical presentation, species distribution and drug susceptibility of patients with NTM disease visiting the Chongqing Public Health Medical Centre during March 2016-April 2019 were retrospectively analysed. Among the 146 patients with NTM disease, eight NTM species (complex) were identified. The predominant NTM species in these patients were identified to be Mycobacterium abscessus complex (53, 36.3%), M. intracellulare (38, 26%) and M. fortuitum (17, 11.7%). In addition, two or more species were isolated from 7.5% of the patients. Pulmonary NTM disease (142, 97.3%) showed the highest prevalence among the patients. It was observed that 40.1% of the patients with pulmonary NTM disease had chronic pulmonary obstructive disease and bronchiectasis, while 22.5% had prior tuberculosis. Male patients showed more association with the conditions of cough and haemoptysis than the female patients. In an in vitro antimicrobial susceptibility testing, most of the species showed susceptibility to linezolid, amikacin and clarithromycin, while M. fortuitum exhibited low susceptibility to tobramycin. In conclusion, the prevalence of NTM disease, especially that of the pulmonary NTM disease, is common in Southwest China. Species identification and drug susceptibility testing are thus extremely important to ensure appropriate treatment regimens for patient care and management.
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http://dx.doi.org/10.1017/S0950268820003088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057515PMC
December 2020

Interactive effects of crab herbivory and spring drought on a Phragmites australis-dominated salt marsh in the Yellow River Delta.

Sci Total Environ 2021 Apr 24;766:144254. Epub 2020 Dec 24.

CAS Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC), Chinese Academy of Sciences (CAS), Yantai, Shandong 264003, PR China; Shandong Key Laboratory of Coastal Environmental Processes, YICCAS, Yantai, Shandong 264003, PR China; CAS Yellow River Delta Ecological Research Station of Coastal Wetland, YICCAS, Yantai, Shandong 264003, PR China. Electronic address:

Consumers are often overlooked as key drivers of vegetation structure and ecosystem functioning in coastal wetlands. This oversight is particularly apparent in Asia, where much of the variation in coastal wetland plant growth and composition is attributed to physical stress gradients. To address this knowledge gap and quantify the relative importance of consumers in Asian coastal wetlands across temporal variation in environmental stress, we conducted a two-year experiment spanning relatively spring wet (2018) and spring dry (2019) years in which we manipulated the presence of the numerically dominant herbivorous crab, Helice tientsinensis, and evaluated its effects on Phragmites australis growth and structure in a Yellow River Delta salt marsh. In spring wetter 2018, Phragmites biomass and stem density were 75% and 34% higher in Crab Exclusion relative to Ambient Crab plots. In 2019 which experienced spring drought and elevated soil salinity, Phragmites biomass and stem density remained similarly high relative to 2018 in Crab Exclusion plots, but fell further, to only 16% and 39% of levels of 2018 observed in Ambient Crab plots. Phragmites' inflorescences density was also significantly reduced in Ambient Crab than Crab Exclusion plots in 2019. Together, these results highlight the significant role that crab herbivores can play in regulating Phragmites in Yellow River Delta salt marshes and suggest that the magnitude of their top-down control may be amplified, although in a non-additive manner, with spring drought stress in the region.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144254DOI Listing
April 2021