Publications by authors named "K K Cheng"

5,617 Publications

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Injectable tricalcium phosphate/calcium sulfate granule enhances bone repair by reversible setting reaction.

Biochem Biophys Res Commun 2021 Apr 14;557:151-158. Epub 2021 Apr 14.

Department of Engineering Sciences: Applied Materials Sciences, The Ångström Laboratory, SE-751 21, Uppsala, Sweden. Electronic address:

Towards repairing bone defects, calcium sulfate and calcium phosphate cement have been recognized as promising bone grafts. However, the current bone cements are generally lack of proper porosity for cell migration and new tissue formation. On the other hand, porous scaffold cannot be delivered by injection, which limits its use its clinical use. Herein, we develop a novel tricalcium phosphate/calcium sulfate granule to overcome the limitations of injectable cements and traditional scaffolds. The biocompatible granule underwent in situ self-setting to form scaffold with porous structure after injection. It contributes to calcium deposition and upregulation of osteogenic genes of mesenchymal stem cells in a time-dependent manner. Within three months, cavitary bone defects of distal rabbit femurs implanted the granules exhibited better bone formation than those with those implanted with autologous bone.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.145DOI Listing
April 2021

SLFN11 inactivation induces proteotoxic stress and sensitizes cancer cells to ubiquitin activating enzyme inhibitor TAK-243.

Cancer Res 2021 Apr 16. Epub 2021 Apr 16.

Center for Cancer Research, Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, National Cancer Institute

Schlafen11 (SLFN11) inactivation occurs in approximately 50% of cancer cell lines and in a large fraction of patient tumor samples, which leads to chemoresistance. Therefore, new therapeutic approaches are needed to target SLFN11-deficient cancers. To that effect, we conducted a drug screen with the NCATS mechanistic drug library of 1978 compounds in isogenic SLFN11-knockout (KO) and wild-type (WT) leukemia cell lines. Here we report that TAK-243, a first-in-class ubiquitin activating enzyme UBA1 inhibitor in clinical development, causes preferential cytotoxicity in SLFN11-KO cells; this effect is associated with claspin-mediated DNA replication inhibition by CHK1 independently of ATR. Additional analyses showed that SLFN11-KO cells exhibit consistently enhanced global protein ubiquitylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and protein aggregation. TAK-243 suppressed global protein ubiquitylation and activated the UPR transducers PERK, phosphorylated eIF2alpha, phosphorylated IRE1, and ATF6 more effectively in SLFN11-KO cells than WT cells. Proteomic analysis using biotinylated mass spectrometry and RNAi screening also showed physical and functional interactions of SLFN11 with translation initiation complexes and protein folding machinery. These findings uncover a previously unknown function of SLFN11 as a regulator of protein quality control and attenuator of ER stress and UPR. Moreover, they suggest the potential value of TAK-243 in SLFN11-deficient tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2694DOI Listing
April 2021

Cognitive insight is correlated with cognitive impairments and contributes to medication adherence in schizophrenia patients.

Asian J Psychiatr 2021 Apr 6;60:102644. Epub 2021 Apr 6.

Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.

Objective: Cognitive insight refers to the ability to distance oneself from and evaluate one's own beliefs and interpretations. Little is known about whether cognitive insight could influence medication adherence in schizophrenia patients. This study examined the role of cognitive insight in medication adherence and how it would interact with neuropsychological functions.

Methods: Ninety clinically-stable schizophrenia patients completed the Beck's Cognitive Insight Scale (BCIS) and tasks measuring prospective (PM) and other neurocognitive functions. Medication adherence was estimated using a multi-axial method comprising interview, clinician-rating, pharmacy refill record and pill counting. Correlational and regression analyses were conducted to examine whether cognitive insight and PM would be associated with mediation adherence. Post-hoc mediational analysis was performed to examine the interplay between cognitive insight, PM and medication adherence.

Results: Clinical insight and cognitive insight together significantly influenced participants' medication adherence, after neurocognitive functions and psychopathology were accounted for. Time-based PM, compared with other neurocognitive functions, affected medication adherence more strongly.

Conclusions: Cognitive insight complements clinical insight in affecting medication adherence in schizophrenia patients.
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http://dx.doi.org/10.1016/j.ajp.2021.102644DOI Listing
April 2021

Cellular Protein Markers, Therapeutics, and Drug Delivery Strategies in the Treatment of Diabetes-Associated Liver Fibrosis.

Adv Drug Deliv Rev 2021 Apr 12. Epub 2021 Apr 12.

Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108. Electronic address:

Liver fibrosis is the excessive accumulation of extracellular matrix due to chronic injuries, such as viral infection, alcohol abuse, high-fat diet, and toxins. Liver fibrosis is reversible before it progresses to cirrhosis and hepatocellular carcinoma. Type 2 diabetes significantly increases the risk of developing various complications including liver diseases. Abundant evidence suggests that type 2 diabetes and liver diseases are bidirectionally associated. Patients with type 2 diabetes experience more severe symptoms and accelerated progression of live diseases. Obesity and insulin resistance resulting from hyperlipidemia and hyperglycemia are regarded as the two major risk factors that link type 2 diabetes and liver fibrosis. This review summarizes possible mechanisms of the association between type 2 diabetes and liver fibrosis. The cellular protein markers that can be used for diagnosis and therapy of type 2 diabetes-associated liver fibrosis are discussed. We also highlight the potential therapeutic agents and their delivery systems that have been investigated for type 2 diabetes-associated liver fibrosis.
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http://dx.doi.org/10.1016/j.addr.2021.04.008DOI Listing
April 2021

Nuclear translocation of ASPL-TFE3 fusion protein creates favorable metabolism by mediating autophagy in translocation renal cell carcinoma.

Oncogene 2021 Apr 12. Epub 2021 Apr 12.

Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China.

The ASPL-TFE3 fusion gene, resulting from t(X;17)(p11.2;q25.3), is one of the most commonly identified fusion genes in Xp11 translocation renal cell carcinoma (tRCC). However, its roles and underlying mechanism in RCC development are not yet clear. Here, we identified ASPL-TFE3 fusion as the most common tRCC subtype in a Chinese population (29/126, 23.03%). This fusion protein translocated into the nucleus and promoted RCC cell proliferation both in vitro and in vivo. Mechanistically, the fusion protein transcriptionally activated the lysosome-autophagy pathway by binding to the promoters of lysosome-related genes. Autophagy, activated by ASPL-TFE3, enabled RCC cells to escape energy stress by promoting the utilization of proteins and lipids. Moreover, we found that the ASPL-TFE3 fusion escaped regulation by the classic mTOR-TFE3 signal and instead activated phospho-mTOR and its downstream targets. Finally, targeting both autophagy and the mTOR axis resulted in a greater antiproliferative effect than single pathway inhibition. In summary, these results confirmed the ASPL-TFE3 fusion as a master regulator of metabolic adaptation mediated by autophagy in tRCC. The simultaneous manipulation of autophagy and the mTOR axis may represent a novel treatment strategy for ASPL-TFE3 fusion RCC.
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http://dx.doi.org/10.1038/s41388-021-01776-8DOI Listing
April 2021

[Diagnosis of large cell neuroendocrine carcinoma by urine cytology: report of a case].

Zhonghua Bing Li Xue Za Zhi 2021 Apr;50(4):408-410

Department of Pathology, Jinling Hospital, Nanjing 210002, China.

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http://dx.doi.org/10.3760/cma.j.cn112151-20201130-00879DOI Listing
April 2021

Cardiac fibrosis: myofibroblast-mediated pathological regulation and drug delivery strategies.

Adv Drug Deliv Rev 2021 Apr 5. Epub 2021 Apr 5.

Department of Molecular Biomedical Sciences, North Carolina State University, North Carolina, USA; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, USA. Electronic address:

Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into myofibroblasts (myoFbs) that are major mediator cells in the pathological remodeling. MyoFbs exhibit proliferative and secretive characteristics, and contribute to extracellular matrix (ECM) turnover, collagen deposition. The persistent functions of myoFbs lead to fibrotic scars and cardiac dysfunction. The anti-fibrotic treatment is hindered by the elusive mechanism of fibrosis and lack of specific targets on myoFbs. In this review, we will outline the progress of cardiac fibrosis and its contributions to the heart failure. We will also shed light on the role of myoFbs in the regulation of adverse remodeling. The communication between myoFbs and other cells that are involved in the heart injury and repair respectively will be reviewed in detail. Then, recently developed therapeutic strategies to treat fibrosis will be summarized such as i) chimeric antigen receptor T cell (CAR-T) therapy with an optimal target on myoFbs, ii) direct reprogramming from stem cells to quiescent CFs, iii) "off-target" small molecular drugs. The application of nano/micro technology will be discussed as well, which is involved in the construction of cell-based biomimic platforms and "pleiotropic" drug delivery systems.
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http://dx.doi.org/10.1016/j.addr.2021.03.021DOI Listing
April 2021

Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study.

Oncologist 2021 Apr 8. Epub 2021 Apr 8.

Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.

Lessons Learned: Bevacizumab combined with S-1 and raltitrexed demonstrated positive anti-tumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer.

Background: In patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed.

Methods: This investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion, were eligible for this trial. Anti-EGFR therapy (for tumors with wild-type RAS) and anti-VEGF in first- or second-line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m on day 1), every 3 weeks. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.

Results: From Sep 2015 to Nov 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated.

Conclusion: Bevacizumab combined with S-1 and raltitrexed showed promising anti-tumor activity and safety in refractory mCRC.
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http://dx.doi.org/10.1002/onco.13778DOI Listing
April 2021

Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology.

Nat Commun 2021 04 6;12(1):2041. Epub 2021 Apr 6.

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Zhongguancun, Beijing, China.

An effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines.
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http://dx.doi.org/10.1038/s41467-021-22308-8DOI Listing
April 2021

All Roads Lead to Rome (the Heart): Cell Retention and Outcomes From Various Delivery Routes of Cell Therapy Products to the Heart.

J Am Heart Assoc 2021 Apr 6:e020402. Epub 2021 Apr 6.

Department of Molecular Biomedical Sciences North Carolina State University Raleigh NC.

In the past decades, numerous preclinical studies and several clinical trials have evidenced the feasibility of cell transplantation in treating heart diseases. Over the years, different delivery routes of cell therapy have emerged and broadened the width of the field. However, a common hurdle is shared by all current delivery routes: low cell retention. A myriad of studies confirm that cell retention plays a crucial role in the success of cell-mediated cardiac repair. It is important for any delivery route to maintain donor cells in the recipient heart for enough time to not only proliferate by themselves, but also to send paracrine signals to surrounding damaged heart cells and repair them. In this review, we first undertake an in-depth study of primary theories of cell loss, including low efficiency in cell injection, "washout" effects, and cell death, and then organize the literature from the past decade that focuses on cell transplantation to the heart using various cell delivery routes, including intracoronary injection, systemic intravenous injection, retrograde coronary venous injection, and intramyocardial injection. In addition to a recapitulation of these approaches, we also clearly evaluate their strengths and weaknesses. Furthermore, we conduct comparative research on the cell retention rate and functional outcomes of these delivery routes. Finally, we extend our discussion to state-of-the-art bioengineering techniques that enhance cell retention, as well as alternative delivery routes, such as intrapericardial delivery. A combination of these novel strategies and more accurate assessment methods will help to address the hurdle of low cell retention and boost the efficacy of cell transplantation to the heart.
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http://dx.doi.org/10.1161/JAHA.120.020402DOI Listing
April 2021

Exosome-eluting stents for vascular healing after ischaemic injury.

Nat Biomed Eng 2021 Apr 5. Epub 2021 Apr 5.

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC, USA.

Drug-eluting stents implanted after ischaemic injury reduce the proliferation of endothelial cells and vascular smooth muscle cells and thus neointimal hyperplasia. However, the eluted drug also slows down the re-endothelialization process, delays arterial healing and can increase the risk of late restenosis. Here we show that stents releasing exosomes derived from mesenchymal stem cells in the presence of reactive oxygen species enhance vascular healing in rats with renal ischaemia-reperfusion injury, promoting endothelial cell tube formation and proliferation, and impairing the migration of smooth muscle cells. Compared with drug-eluting stents and bare-metal stents, the exosome-coated stents accelerated re-endothelialization and decreased in-stent restenosis 28 days after implantation. We also show that exosome-eluting stents implanted in the abdominal aorta of rats with unilateral hindlimb ischaemia regulated macrophage polarization, reduced local vascular and systemic inflammation, and promoted muscle tissue repair.
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http://dx.doi.org/10.1038/s41551-021-00705-0DOI Listing
April 2021

Microfluid-based soft metasurface for tunable optical activity in THz wave.

Opt Express 2021 Mar;29(6):8786-8795

Metasurfaces are usually planar structures and do not possess intrinsic chirality and therefore hardly generate optical activity. Here we realized a tunable optical activity in a terahertz wave through a microfluid-based soft metasurface. The meta-atom is a chiral structured microchannel made of soft polydimethylsiloxane and injected with the liquid metal Galinstan. A microfluid pressure system is bonded to the metasurface to reconfigure all meta-atoms simultaneously. By pumping glycerol liquid into the pressure system, the metasurface is deformed from a planar structure to a three dimensional one, which manifests intrinsic chirality for optical activity realization. By controlling the injected glycerol volume, a polarization rotation from 0°to 14° at 0.19 THz is demonstrated. The soft metasurface with tunable optical activity can be flexibly applied in various applications such as polarization microscopy, bio-detection and material analysis, etc.
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http://dx.doi.org/10.1364/OE.420660DOI Listing
March 2021

Panchromatic Image Super-Resolution Via Self Attention-Augmented Wasserstein Generative Adversarial Network.

Sensors (Basel) 2021 Mar 19;21(6). Epub 2021 Mar 19.

Xidian School of Physics and Optoelectronic Engineering, Xidian University, Xi'an 710071, China.

Panchromatic (PAN) images contain abundant spatial information that is useful for earth observation, but always suffer from low-resolution ( LR) due to the sensor limitation and large-scale view field. The current super-resolution (SR) methods based on traditional attention mechanism have shown remarkable advantages but remain imperfect to reconstruct the edge details of SR images. To address this problem, an improved SR model which involves the self-attention augmented Wasserstein generative adversarial network ( SAA-WGAN) is designed to dig out the reference information among multiple features for detail enhancement. We use an encoder-decoder network followed by a fully convolutional network (FCN) as the backbone to extract multi-scale features and reconstruct the High-resolution (HR) results. To exploit the relevance between multi-layer feature maps, we first integrate a convolutional block attention module (CBAM) into each skip-connection of the encoder-decoder subnet, generating weighted maps to enhance both channel-wise and spatial-wise feature representation automatically. Besides, considering that the HR results and LR inputs are highly similar in structure, yet cannot be fully reflected in traditional attention mechanism, we, therefore, designed a self augmented attention (SAA) module, where the attention weights are produced dynamically via a similarity function between hidden features; this design allows the network to flexibly adjust the fraction relevance among multi-layer features and keep the long-range inter information, which is helpful to preserve details. In addition, the pixel-wise loss is combined with perceptual and gradient loss to achieve comprehensive supervision. Experiments on benchmark datasets demonstrate that the proposed method outperforms other SR methods in terms of both objective evaluation and visual effect.
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http://dx.doi.org/10.3390/s21062158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003560PMC
March 2021

Cardiac Cell Therapy for Heart Repair: Should the Cells Be Left Out?

Cells 2021 Mar 13;10(3). Epub 2021 Mar 13.

Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA.

Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary artery occlusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia area is eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronic transduction, contraction and compliance, pathological cardiac dilation and heart failure develops. Once end-stage heart failure occurs, the only option is to perform heart transplantation. The sequential changes are termed cardiac remodeling, and are due to the lack of endogenous regenerative actions in the adult human heart. Regenerative medicine and biomedical engineering strategies have been pursued to repair the damaged heart and to restore normal cardiac function. Such strategies include both cellular and acellular products, in combination with biomaterials. In addition, substantial progress has been made to elucidate the molecular and cellular mechanisms underlying heart repair and regeneration. In this review, we summarize and discuss current therapeutic approaches for cardiac repair and provide a perspective on novel strategies that holding potential opportunities for future research and clinical translation.
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http://dx.doi.org/10.3390/cells10030641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999733PMC
March 2021

Reducing refractory angina.

EuroIntervention 2021 Apr 2;16(18):e1466-e1467. Epub 2021 Apr 2.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.4244/EIJV16I18A265DOI Listing
April 2021

Development of a Cancer Vaccine Using In Vivo Click-Chemistry-Mediated Active Lymph Node Accumulation for Improved Immunotherapy.

Adv Mater 2021 Mar 31:e2006007. Epub 2021 Mar 31.

CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, China, Beijing, 100190, China.

Due to their ability to elicit a potent immune reaction with low systemic toxicity, cancer vaccines represent a promising strategy for treating tumors. Considerable effort has been directed toward improving the in vivo efficacy of cancer vaccines, with direct lymph node (LN) targeting being the most promising approach. Here, a click-chemistry-based active LN accumulation system (ALAS) is developed by surface modification of lymphatic endothelial cells with an azide group, which provide targets for dibenzocyclooctyne (DBCO)-modified liposomes, to improve the delivery of encapsulated antigen and adjuvant to LNs. When loading with OVA peptide and poly(I:C), the formulation elicits an enhanced CD8 T cell response in vivo, resulting in a much more efficient therapeutic effect and prolonged median survival of mice. Compared to treatment with DBCO-conjugated liposomes (DL)-Ag/Ad without the azide targeting, the percent survival of ALAS-vaccine-treated mice improves by 100% over 60 days. Altogether, the findings indicate that the novel ALAS approach is a powerful strategy to deliver vaccine components to LNs for enhanced antitumor immunity.
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http://dx.doi.org/10.1002/adma.202006007DOI Listing
March 2021

Efficacy of abdominal ultrasound inspection in the diagnosis and prognosis of neonatal necrotizing enterocolitis.

Clinics (Sao Paulo) 2021 26;76:e1816. Epub 2021 Mar 26.

Department of Neonatology, Gansu Provincial Maternity and Child Care Hospital, Lanzhou, 730050, China.

Objective: This study aimed to identify the most useful ultrasound (US) features associated with definite neonatal necrotizing enterocolitis (NEC) and their prognostic values, particularly the calculated markers combined with important features.

Methods: A total of 213 suspected NEC cases were collected from the neonatal department of our hospital from January 2015 to August 2017. Each infant received both X-ray and US examinations.

Results: No differences were found in sex composition and delivery modes between groups. NEC-positive neonates had poorer prognosis compared to negative ones. The NEC group showed a higher frequency of abnormal signals. US showed higher NEC-related frequencies in different parameters. A variable (named predictor in US [PUS]) with five features was constructed. For NEC diagnosis, this variable provided a much higher area under the curve Q2 (AUC) (0.965) than other parameters. In this model, PUS had a cutoff value of 0.376 with a 0.900 sensitivity and 0.922 specificity. In prognosis, the closest factors were selected to draw a receiver operating characteristic curve, as well as a novel calculated variable US prognostic (USPro) marker. USPro had a much higher AUC (0.86) than other single features and showed a cutoff value of 0.18145, with 0.75 sensitivity and 0.84 specificity. This variable had a weaker power in prognosis when compared with PUS in diagnosis.

Conclusions: The application of abdominal color Doppler US can provide high accuracy and sensitivity in NEC diagnosis and also contribute to its prognosis, without induction of radiation. Suspected neonates should be examined using this technique as early as possible.
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http://dx.doi.org/10.6061/clinics/2021/e1816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978842PMC
March 2021

Gene Expression, Biochemical Characterization of a sn-1, 3 Extracellular Lipase From GZUF36 and Its Model-Structure Analysis.

Front Microbiol 2021 12;12:633489. Epub 2021 Mar 12.

Key Laboratory of Agricultural and Animal Products Store and Processing of Guizhou Province, Guizhou University, Guiyang, China.

In this study, a sn-1, 3 extracellular lipases from GZUF36 (PEXANL1) was expressed in , characterized, and the predicted structural model was analyzed. The optimized culture conditions of showed that the highest lipase activity of 66.5 ± 1.4 U/mL ( < 0.05) could be attained with 1% methanol and 96 h induction time. The purified PEXANL1 exhibited the highest activity at pH 4.0 and 40°C temperature, and its original activity remained unaltered in the majority of the organic solvents (20% v/v concentration). Triton X-100, Tween 20, Tween 80, and SDS at a concentration of 0.01% (w/v) enhanced, and all the metal ions tested inhibited activity of purified PEXANL. The results of ultrasound-assisted PEXANL1 catalyzed synthesis of 1,3-diaglycerides showed that the content of 1,3-diglycerides was rapidly increased to 36.90% with 25 min of ultrasound duration ( < 0.05) and later decreased to 19.93% with 35 min of ultrasound duration. The modeled structure of PEXANL1 by comparative modeling showed α/β hydrolase fold. Structural superposition and molecular docking results validated that Ser162, His274, and Asp217 residues of PEXANL1 were involved in the catalysis. Small-angle X-ray scattering analysis indicated the monomer properties of PEXANL1 in solution. The model of PEXANL1 overlapped with its modeling structure. This work presents a reliable structural model of lipase based on homology modeling and small-angle X-ray scattering. Besides, the data from this study will benefit the rational design of suitable crystalline lipase variants in the future.
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http://dx.doi.org/10.3389/fmicb.2021.633489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994357PMC
March 2021

Non-invasive early detection of failure modes in total hip replacements (THR) via acoustic emission (AE).

J Mech Behav Biomed Mater 2021 Mar 19;118:104484. Epub 2021 Mar 19.

RMDR Lab, Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL, USA. Electronic address:

Total hip replacements (THR) are becoming an common orthopedic surgucal procedure in the United States (332 K/year in 2017) to relieve pain and improve the mobility of those that are affected by osteoarthritis, ankylosing spondylitis, or injury. However, complications like tribocorrosion, or material degradation due to friction and corrosion, may result in THR failure. Unfortunately, few strategies to non-invasively diagnose early-stage complications are reported in literature, leading to implant complications being detected after irreversible damage. Therefore, the main objective of this study proposes the utilization of acoustic emission (AE) to continuously monitor implant materials, CoCrMo and Ti6Al4V, and identify degradations formed during cycles of sleeping, standing, and walking by correlating them to potential and friction coefficient behavior. AE activity detected from the study correlates with the friction coefficient and open-circuit potential observed during recreated in-vitro standing, walking, and sleeping cycles. It was found that the absolute energy level obtained from AE increased as the friction coefficient increased, potential decreased, and wear volume loss increased. Through the results, higher friction coefficient and AE activity were observed in Ti6Al4V alloys while there was also a significant drop in potential, indicating increased tribocorrosion activity. Therefore, AE can be utilized to predict material degradations as a non-invasive method based on the severity of abnormality of the absolute energy and hits emitted. The correlation between potential, friction coefficient, and AE activity was further confirmed through profilometry which showed more material degradation in Ti6Al4V than CoCrMo. Through these evaluations, it was demonstrated that AE could be utilized to identify the deformations and failure modes of implant materials caused by tribocorrosion.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104484DOI Listing
March 2021

Ferritin disorder in the plasma and hippocampus associated with major depressive disorder.

Biochem Biophys Res Commun 2021 May 22;553:114-118. Epub 2021 Mar 22.

NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402460, China; Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China. Electronic address:

Major depressive disorder (MDD) is a debilitating mental illness that can cause significant emotional disturbances and severe socioeconomic burdens. Rodent and nonhuman primate-based depression models have been studied, such as brain-derived neurotrophic factor (BDNF) and monoamine acid disorder hypotheses, as well as peripheral microbiota disturbances causing MDD; however, the pathogenesis is still largely unknown. This study aims to explore the relationship between ferritin and MDD. First, alterations in ferritin, including ferritin light chain (FTL) and ferritin heavy chain (FTH), in MDD patient plasma compared with healthy control (HC) plasma were detected using ELISA. Then, serum ferritin expression in cLPS-depressed mice was measured by ELISA. The existence of FTH in the hippocampus was validated by immunofluorescence, and the change in FTH levels in the hippocampus of mice injected with cLPS was detected by western blotting. FTL levels in MDD patients were decreased compared with those in HCs. In cLPS-depressed mice, serum ferritin was not different from that in the control group, while the expression of FTH in the hippocampus was significantly reduced in depressed mice. Our findings demonstrate the alteration of ferritin expression in MDD and provide new insight into the pathogenesis of MDD.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.059DOI Listing
May 2021

LMO7 as an Unrecognized Factor Promoting Pancreatic Cancer Progression and Metastasis.

Front Cell Dev Biol 2021 8;9:647387. Epub 2021 Mar 8.

Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.

Pancreatic cancer (PC) is one of the most lethal human malignancies without effective treatment. In an effort to discover key genes and molecular pathways underlying PC growth, we have identified LIM domain only 7 (LMO7) as an under-investigated molecule, which highly expresses in primary and metastatic human and mouse PC with the potential of impacting PC tumorigenesis and metastasis. Using genetic methods with siRNA, shRNA, and CRISPR-Cas9, we have successfully generated stable mouse PC cells with LMO7 knockdown or knockout. Using these cells with loss of LMO7 function, we have demonstrated that intrinsic LMO7 defect significantly suppresses PC cell proliferation, anchorage-free colony formation, and mobility and slows orthotopic PC tumor growth and metastasis . Mechanistic studies demonstrated that loss of LMO7 function causes PC cell-cycle arrest and apoptosis. These data indicate that LMO7 functions as an independent and unrecognized druggable factor significantly impacting PC growth and metastasis, which could be harnessed for developing a new targeted therapy for PC.
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http://dx.doi.org/10.3389/fcell.2021.647387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982467PMC
March 2021

Inhibition of HECT E3 ligases as potential therapy for COVID-19.

Cell Death Dis 2021 03 24;12(4):310. Epub 2021 Mar 24.

Department of Pathology, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA, 02215, USA.

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.
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http://dx.doi.org/10.1038/s41419-021-03513-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987752PMC
March 2021

Effects of long-term fertilizer management on soil labile organic carbon fractions and hydrolytic enzyme activity under a double-cropping rice system of southern China.

Ying Yong Sheng Tai Xue Bao 2021 Mar;32(3):921-930

Hunan Soil and Fertilizer Institute, Changsha 410125, China.

Fertilization is an effective way to improve soil quality, increase soil fertility and soil microbial diversity in paddy soil. To explore the changes of soil labile organic carbon (C) fractions and hydrolytic enzyme activity after 34 years fertilization treatments in a field experiment in double-cropping rice system of southern China. There were four treatments, including chemical fertilizer alone (MF), rice residue and chemical fertilizer (RF), 30% organic matter and 70% chemical fertilizer (OM), and the control without fertilizer input (CK). We measured soil organic carbon (SOC) content, soil labile organic C fractions, SOC related hydrolytic enzyme activity, correlation coefficients of soil enzyme activity with SOC content and its labile organic C fractions. The results showed that MF, RF and OM increased SOC content by 4.5%, 22.4% and 53.5%, respectively. Compared with MF and CK, RF and OM increased soil labile organic C fractions [cumulative C mineralization (Cmin), permanganate oxidizable C (KMnO-C), particulate organic C (POC), dissolved organic C (DOC), light fraction organic C (LFOC), microbial biomass C (MBC)] and the proportion of each labile organic C fractions to total organic C. The contents of Cmin, KMnO-C, POC, DOC, LFOC and MBC under OM treatment were 3.5, 3.1, 3.7, 1.9, 1.2 and 1.9 times higher than CK treatment, respectively. The proportion of labile organic C fractions to total organic C of RF and OM treatments was significantly higher than that in CK. The order of soil hydrolytic enzyme activity [α-glucosidase (αG), β-glucosidase (βG), β-xylosidase (βX), cellobiohydrolase (GBH), and N-acetyl-β-glucosaminidase (NAG)] was OM>RF>MF>CK. The soil hydrolytic enzyme activity under OM treatment increased by 111.8%, 14.1%, 127.3%, 285.6% and 91.4% compared with CK, respectively. Furthermore, RF and OM treatments were beneficial to soil peroxidase (POD) activity. MF treatment was beneficial to soil polyphenol oxidase (PPO) activity. There was a significant positive correlation between soil hydrolytic enzyme activity and SOC content and its labile organic C fractions. In conclusion, the combined application of organic manure, rice straw returning and chemical fertilizer is an effective method to improve soil labile organic C fractions and hydrolytic enzyme activity in a double-cropping rice paddy field of southern China.
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http://dx.doi.org/10.13287/j.1001-9332.202103.023DOI Listing
March 2021

Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice p53/PPARα signaling.

Theranostics 2021 4;11(10):4710-4727. Epub 2021 Mar 4.

State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Telomere shortening and dysfunction may cause metabolic disorders, tissue damage and age-dependent pathologies. However, little is known about the association of telomere-associated protein Rap1 with mitochondrial energy metabolism and cardiac aging. Echocardiography was performed to detect cardiac structure and function in Rap1 and Rap1 mice at different ages (3 months, 12 months and 20 months). Telomere length, DNA damage, cardiac senescence and cardiomyocyte size were analyzed using the real-time PCR, Western blotting, senescence associated β-galactosidase assay and wheat germ agglutinin staining, respectively. Western blotting was also used to determine the level of cardiac fatty acid metabolism related key enzymes in mouse and human myocardium. Chromatin immunoprecipitation assay was used to verify the direct link between p53 and PPARα. The p53 inhibitor, Pifithrin-α and PPARα activator WY14643 were utilized to identify the effects of Rap1/p53/PPARα signaling pathway. Telomere was shortened concomitant with extensive DNA damage in aged Rap1 mouse hearts, evidenced by reduced T/S ratios and increased nuclear γH2AX. Meanwhile, the aging-associated phenotypes were pronounced as reflected by altered mitochondrial ultrastructure, enhanced senescence, cardiac hypertrophy and dysfunction. Mechanistically, acetylated p53 and nuclear p53 was enhanced in the Rap1 mouse hearts, concomitant with reduced PPARα. Importantly, p53 directly binds to the promoter of PPARα in mouse hearts and suppresses the transcription of PPARα. In addition, aged Rap1 mice exhibited reduced cardiac fatty acid metabolism. Pifithrin-α alleviated cardiac aging and enhanced fatty acid metabolism in the aged Rap1 mice. Activating PPARα with WY14643 in primarily cultured Rap1 cardiomyocytes restored maximal oxygen consumption rates. Reduced Rap1 expression and impaired p53/PPARα signaling also presented in aged human myocardium. In summary, Rap1 may link telomere biology to fatty acid metabolism and aging-related cardiac pathologies modulating the p53/PPARα signaling pathway, which could represent a therapeutic target in preventing/attenuating cardiac aging.
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http://dx.doi.org/10.7150/thno.51739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978321PMC
March 2021

Improved thermal/chemical stability of flexible Ag NWs/Chitosan composite electrode integrated by chemical welding and sequential protection for better PV performance.

Nanotechnology 2021 Mar 22. Epub 2021 Mar 22.

Key Lab for Special Functional Materials of Ministry of Education, Collaborative Innovation Center of Nano Functional Materials and Applications, Kaifeng, CHINA.

An integration strategy of chemical welding and subsequent protection was demonstrated to address silver nanowires (Ag NWs)-based issues. Preferentially, a halogenated salt of NaCl solution was used to stimulate the junction welding thus to reduce the junction resistance, by virtue of the autocatalytic redox of Ag atoms with halogen ions and dissolved oxygen molecules. Subsequently, chitosan, possessing the biocompatible, degradable, environmentally friendly non-toxic features, was embedded to protect Ag NWs. With these two steps, the composite electrode consisting Ag NWs and chitosan reaches a lowest sheet resistance of ~8 Ω, with a transmittance over 80% at 550 nm, along with high thermal and chemical stabilities, accompanying with excellent flexibility. Besides, it also prompts a synergistic improvement when pioneered in Cu(In, Ga)Se2 (CIGS) device as a transparent conductive electrode (TCE). It yields a power conversion efficiency of 6.6%, with 32% improvement relative to that bare Ag NWs, and 85% of the conventional one. Our findings present a new strategy for addressing instable/inefficient Ag NWs-based devices, driving their rapid development and its practical applications.
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http://dx.doi.org/10.1088/1361-6528/abf0caDOI Listing
March 2021

Safety, Efficacy, and Pharmacokinetics of Metatinib Tromethamine Tablet in Patients with Advanced Refractory Solid Tumors: A Phase I Clinical Trial.

Oncologist 2021 Mar 22. Epub 2021 Mar 22.

Institute of Clinical Pharmacology, GCP, Center.

Lessons Learned: MET overexpression is uncommon, and positive MET immunohistochemistry (1+/2+) was an independent positive prognostic factor for RR and progression-free survival. Whether MET overexpression can be considered a potential predictive biomarker and be used as an inclusion criterion is worth investigating in a future study.

Background: Metatinib tromethamine tablet (metatinib) is a small molecule receptor kinase inhibitor targeting both c-MET and vascular endothelial growth factor receptor 2. This phase I trial aimed to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), pharmacokinetics, safety, and efficacy of metatinib in patients with advanced solid tumors.

Methods: Eligible patients received a single dose of metatinib in a 3+3 dose-escalation design with dose levels of 25-800 mg/day, after a single dose on day 1, then 2 days off, and then a multidose schedule of once-daily doses for 25 consecutive days (days 4-28). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), efficacy, and biomarkers.

Results: Eighteen patients (including nine patients with hepatocellular carcinoma [HCC]) received at least one dose of study drug (one patient quit the study without continuous multiple-dose administration after receiving a single dose of metatinib). Hand-foot skin reaction, diarrhea, and liver dysfunction were the DLTs, and 200 mg/day was the MTD. The most common treatment-related adverse events (TRAEs) were skin toxicity (50%), diarrhea (33.3%), and liver dysfunction (27.8%). Three patients (only one of six in the 200 mg/day cohort; the other two in the 300 mg/day cohort) experienced severe TRAEs: one patient with severe liver dysfunction and two patients with severe liver dysfunction and skin toxicity, respectively. Pharmacokinetics assessment indicated that metatinib was rapidly absorbed and metabolized to the formation of reactive metabolite, SCR-1510, after single-dose administration. The mean time taken to achieve maximum concentration and terminal elimination half-life of SCR-1510 was approximately 2.0-3.0 hours and ranged from 8 to 14 hours. Two patients had partial responses. The ORR and disease control rate (DCR) were 11.1% and 61.1%, respectively. The median progression-free survival (PFS) was 2.75 months.

Conclusion: Metatinib administration of 200 mg/day was well tolerated, safe, and effective. The MTD was 200 mg/day, which should be recommended in further investigations.
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http://dx.doi.org/10.1002/onco.13760DOI Listing
March 2021

Silk fibroin H-fibroin/poly(ε-caprolactone) core-shell nanofibers with enhanced mechanical property and long-term drug release.

J Colloid Interface Sci 2021 Mar 9;593:142-151. Epub 2021 Mar 9.

School of Materials Science and Engineering and Institute for Advanced Materials, Jiangsu University, Zhenjiang 212013, China. Electronic address:

The scaffold materials with good mechanical and structural properties, controlled drug release performance, biocompatibility and biodegradability are important tenet in tissue engineering. In this work, the functional core-shell nanofibers with poly(ε-caprolactone) (PCL) as shell and silk fibroin heavy chain (H-fibroin) as core were constructed by emulsion electrospinning. The transmission electron microscopy confirmed that the nanofiber with core-shell structure were successfully prepared. The constructed nanofiber materials were characterized by the several characterization methods. The results showed that ethanol treatment could induce the formation of β-sheet of H-fibroin in composite nanofibers, thus improving the mechanical properties of PCL/H-fibroin nanofiber scaffold. In addition, we evaluated the potential of PCL/H-fibroin nanofiber membrane as a biological scaffold. It was found that PCL/H-fibroin nanofiber scaffold was more conducive to cell adhesion and proliferation with the increment of H-fibroin. Finally, in vitro drug release presented that PCL/H-fibroin core-shell nanofibers could effectively reduce the prophase burst of drug molecules and show the sustained drug release. The PCL/H-fibroin nanofiber scaffolds constructed in this work have good mechanical properties, biocompatibility, and display good potential in biomedical applications, such as drug carriers, tissue engineering and wound dressings, etc.
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http://dx.doi.org/10.1016/j.jcis.2021.02.099DOI Listing
March 2021

Long non-coding RNA KCNQ1OT1 promotes hydrogen peroxide-induced lens epithelial cell apoptosis and oxidative stress by regulating miR-223-3p/BCL2L2 axis.

Authors:
Min Zhang Kai Cheng

Exp Eye Res 2021 Mar 17;206:108543. Epub 2021 Mar 17.

Department of Ophthalmology, Jinan Maternal and Child Health Hospital, Jinan, 250001, Shandong, China. Electronic address:

Many long non-coding RNAs (lncRNAs) can exert crucial roles in the pathogenesis of cataract, including lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1). We aimed to further elucidate the biological role and regulatory molecular mechanism of KCNQ1OT1 in cataract. The expression of KCNQ1OT1 and miR-223-3p and BCL2 like 2 (BCL2L2) was examined by qRT-PCR. Cataract cell model was constructed by treatment with hydrogen peroxide (HO) in lens epithelial cells (SRA01/04). SRA01/04 cell viability and cell apoptosis were tested using CCK-8 assay and flow cytometry, respectively. Western blot (WB) was performed to measure the levels of apoptosis-related proteins and BCL2L2 protein. The oxidative stress factors were analyzed by corresponding kits. The interaction between miR-223-3p and KCNQ1OT1 or BCL2L2 was validated by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. We found that KCNQ1OT1 was upregulated in cataract anterior lens capsule samples and HO-induced SRA01/04 cells. Knockdown of KCNQ1OT1 suppressed HO-induced SRA01/04 cell apoptosis and oxidative stress. KCNQ1OT1 acted as a sponge of miR-223-3p. Inhibition of miR-223-3p could abate the function of KCNQ1OT1 silence in HO-treated SRA01/04 cells. Additionally, BCL2L2 was a direct target of miR-223-3p, and miR-223-3p weakened HO-induced SRA01/04 cell apoptosis and oxidative stress by targeting BCL2L2. Collectively, the data suggest a role for the KCNQ1OT1/miR-223-3p/BCL2L2 axis in cataract formation but the data was generated using an epithelial cell line.
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http://dx.doi.org/10.1016/j.exer.2021.108543DOI Listing
March 2021

Sustainable advances on phosphorus utilization in soil via addition of biochar and humic substances.

Sci Total Environ 2021 May 29;768:145106. Epub 2021 Jan 29.

State Key Laboratory of Geomechanics and Geotechnical Engineering, Institute of Rock and Soil Mechanics, Chinese Academy of Sciences, Wuhan 430071, China. Electronic address:

The intervention of human in phosphorus pool seems to be a vicious circle. The rapid population growth leads to the global food shortage, which leads to the massive use of phosphate fertilizer and the continuous exploitation of phosphate rocks. With the massive loss and fixation of phosphate fertilizer in the soil, the unavailable phosphorus in the soil becomes superfluous, while the phosphate mineral resources turn to scarce. Interestingly, exogenous carbonaceous materials, notably, biochar and humic substances, have been widely used as soil conditioners in agricultural production up to date, among other actions to interfere with the balance between the different phosphate species, which offer effective roles for increasing soil available phosphorus. This article reviews the regulation mechanisms of biochar and humic substances on phosphorus availability and circulation, including improving soil physicochemical characteristics, regulating microbial community structure, and directly interacting with phosphorus to affect the fate of phosphorus in soil. Finally, the prospects for future research directions are made, and it is hoped that the review of this article can arouse people's attention to the current plight of agricultural production and provide some methods for improving the efficiency of phosphate fertilizer use in the future.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145106DOI Listing
May 2021