Publications by authors named "Zhijun Liu"

253 Publications

CMP25, a synthetic new agent, targets multidrug resistance-associated protein 7 (MRP7/ABCC10).

Biochem Pharmacol 2021 Jun 11:114652. Epub 2021 Jun 11.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA. Electronic address:

Multidrug resistance-associated protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to mediate the cross-membrane translocation of a wide range of chemotherapeutic agents including taxanes, epothilones, Vinca alkaloids, Anthracyclines and Epipodophyllotoxins.In our previous study, a 1,2,3-triazole-pyrimidine hybridCMP25was synthesized and found able to efficiently reverse multidrug resistance (MDR) mediated by P-glycoprotein. In this study, we evaluated the efficacy of compound CMP25in reversing MDR mediated by MRP7in vitro. The results showed that CMP25significantly sensitized MRP7-overexpressing cells to anticancer drugs that are MRP7 substrates. Mechanistic study showed that CMP25reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or subcellular localization. Currently, very few studies on synthetic MRP7 modulators have been published. Our findings provide a valuable prototype for designing drugs to combine with conventional anticancer drugs to overcome MDR-mediated by MRP7.
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http://dx.doi.org/10.1016/j.bcp.2021.114652DOI Listing
June 2021

An amphipathic Bax core dimer forms part of the apoptotic pore wall in the mitochondrial membrane.

EMBO J 2021 Jun 8:e106438. Epub 2021 Jun 8.

State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.

Bax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. This might involve their embedding in the cytosolic leaflet of the lipid bilayer, thus generating tension to induce a lipid pore with radially arranged lipids forming the wall. Alternatively, Bax proteins might comprise part of the pore wall. However, there is no unambiguous structural evidence for either hypothesis. Using NMR, we determined a high-resolution structure of the Bax core region, revealing a dimer with the nonpolar surface covering the lipid bilayer edge and the polar surface exposed to water. The dimer tilts from the bilayer normal, not only maximizing nonpolar interactions with lipid tails but also creating polar interactions between charged residues and lipid heads. Structure-guided mutations demonstrate the importance of both types of protein-lipid interactions in Bax pore assembly and core dimer configuration. Therefore, the Bax core dimer forms part of the proteolipid pore wall to permeabilize mitochondria.
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http://dx.doi.org/10.15252/embj.2020106438DOI Listing
June 2021

Free vastus lateralis muscle flap transplantation for postoperative chronic empyema: retrospective analysis of eight case series.

Ann Palliat Med 2021 May 14;10(5):5046-5054. Epub 2021 May 14.

Department of Cardiothoracic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China.

Background: Postoperative chronic empyema (PPE) remains a complex challenge for thoracic surgeons. We retrospectively investigated patients with PPE who were treated with free vastus lateralis muscle flap transplantation, and report our results.

Methods: Eight patients with PPE and persistent bronchopleural fistula (BPF) treated in our hospital from January 2015 to June 2019 were retrospectively analyzed, the time since onset of empyema ranged from 5 to 72 months. The operation was performed in two stages, stage I surgery included empyema debridement, rib resection drainage or open-window thoracostomy (OWT), meanwhile, BPF was treated under bronchoscope. Stage II surgery included obliteration of the pleural space by free muscle flap transplantation. The keys to the operation are thorough debridement, closure of the BPF, and complete obliteration of the residual pleural space. The challenge lies in the anastomosis of the lateral femoral circumflex artery and vein that supply the vastus lateralis muscle flap to the thoracodorsal vessels.

Results: The free muscle flaps survived in all eight patients. The abscess cavity was completely obliterated with the muscle flap. Good efficacy was achieved with primary wound healing. No serious perioperative complications were reported. No empyema recurrence, atrophy, infection, or necrosis of the muscle flap was seen during the 18- to 72-month follow-up.

Conclusions: The vastus lateralis muscle flap has a large volume with good blood supply and strong antibacterial ability. It can be used for effective obliteration of a large residual cavity caused by empyema and maintains a good thoracic shape. It is an ideal choice for the treatment of postoperative chronic refractory empyema.
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http://dx.doi.org/10.21037/apm-21-261DOI Listing
May 2021

The Amplatzer device and pedicle muscle flap transposition for the treatment of bronchopleural fistula with chronic empyema after lobectomy: two case reports.

World J Surg Oncol 2021 May 26;19(1):158. Epub 2021 May 26.

Department of General Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China.

Background: Bronchopleural fistula (BPF) refers to an abnormal channel between the pleural space and the bronchial tree. It is a potentially fatal postoperative complication after pulmonary resection and a complex challenge for thoracic surgeons because many patients with BPF ultimately develop refractory empyema, which is difficult to manage and has a major impact on quality of life and survival. Therefore, an operative intervention combined with conservative and endoscopic therapies may be required to control infection completely, to occlude BPF, and to obliterate the empyema cavity during treatment periods.

Case Presentation: Two patients who suffered from BPF complicated with chronic empyema after lobectomy were treated in other hospitals for a long time and did not recover. In our department, we performed staged surgery and creatively combined an Amplatzer Septal Occluder (ASO) device (AGA Medical Corp, Golden Valley, MN, USA) with pedicled muscle flap transposition. First, open-window thoracostomy (OWT), or effective drainage, was performed according to the degree of contamination in the empyema cavity after the local infection was controlled. Second, Amplatzer device implantation and pedicled muscle flap transposition was performed at the same time, which achieved the purpose of obliterating the infection, closing the fistula, and tamponading the residual cavity. The patients recovered without complications and were discharged with short hospitalization stays.

Conclusions: We believe that the union of the Amplatzer device and pedicle muscle flap transposition seems to be a safe and effective treatment for BPF with chronic empyema and can shorten the length of the related hospital stay.
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http://dx.doi.org/10.1186/s12957-021-02270-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157618PMC
May 2021

Preparation and Characterization of Cellulose Composite Hydrogels From Tea Residue and Single-Walled Carbon Nanotube Oxides and Its Potential Applications.

Front Chem 2021 4;9:651566. Epub 2021 May 4.

Guangdong Polytechnic of Science and Trade, Guangzhou, China.

Hydrogels were prepared from tea cellulose with the addition of single-walled carbon nanotube oxides in 1-allyl-3-methylimidazolium chloride. Single-walled carbon nanotube oxides/tea cellulose hydrogels (TCH-SWNTs) were characterized by Fourier transform infrared, x-ray diffraction, texture profile analysis, and thermogravimetric analysis. The adsorption capacity of methylene blue using the prepared hydrogels was also investigated. The hydrogels exhibited greater thermal stability and intensive textural property with the addition of single-walled carbon nanotube oxides. Compared with undoped TCHs, the weight loss peak moved from 280 to 323°C, and the values of hardness, fracturability, gumminess, and resilience were 8.4, 5.3, 10.8, and 1.9, respectively, times higher than that of TCHs. As an absorbent of methylene blue, TCH-SWNTs accorded to a pseudo-second-order kinetic model, good adsorption capacity (13.8 mg/g), and good adsorption ratio (27.59%) and showed potential as a drug carrier.
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http://dx.doi.org/10.3389/fchem.2021.651566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129011PMC
May 2021

Cynaroside prevents macrophage polarization into pro-inflammatory phenotype and alleviates cecal ligation and puncture-induced liver injury by targeting PKM2/HIF-1α axis.

Fitoterapia 2021 Jul 11;152:104922. Epub 2021 May 11.

College of Life Science, Zhejiang Chinese Medical University, 310053 Hangzhou, China. Electronic address:

The treatment of sepsis is still challenging and the liver is an important target of sepsis-related injury. Macrophages are important innate immune cells in liver, and modulation of macrophages M1/M2 polarization may be a promising strategy for septic liver injury treatment. Macrophage polarization and inflammation of liver tissue has been shown regulated by pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis and immune inflammatory pathways. Therefore, modulating PKM2-mediated immunometabolic reprogramming presents a novel strategy for inflammation-associated diseases. In this study, cynaroside, a flavonoid compound, promoted macrophage phenotypic transition from pro-inflammatory M1 to anti-inflammatory M2, and mitigated sepsis-associated liver inflammatory damage. We established that cynaroside reduced binding of PKM2 to hypoxia-inducible factor-1α (HIF-1α) by abolishing translocation of PKM2 to the nucleus and promoting PKM2 tetramer formation, as well as suppressing phosphorylation of PKM2 at Y105 in vivo and in vitro. Moreover, cynaroside restored pyruvate kinase activity, inhibited glycolysis-related proteins including PFKFB3, HK2 and HIF-1α, and inhibited glycolysis-related hyperacetylation of HMGB1 in septic liver. Therefore, this study reports a novel function of cynaroside in hepatic macrophage polarization, and cecum ligation and puncture-induced liver injury in septic mice. The findings provide crucial information with regard to therapeutic efficacy of cynaroside in the treatment of sepsis.
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http://dx.doi.org/10.1016/j.fitote.2021.104922DOI Listing
July 2021

Congenital Human Cytomegalovirus Infection Inducing Sensorineural Hearing Loss.

Front Microbiol 2021 14;12:649690. Epub 2021 Apr 14.

Department of Microbiology, Weifang Medical University, Weifang, China.

Human cytomegalovirus (HCMV) is the primary cause of congenital infections. Despite its clinical significance, congenital HCMV infection is frequently overlooked clinically since most affected infants are asymptomatic. Sensorineural hearing loss (SNHL) is one of the most widely known disorders caused by congenital HCMV infection. The potential mechanism, however, remains unknown to date. The mechanism by which congenital HCMV infection induces sensorineural deafness has been partly characterized, leading to advancements in diagnosis, therapy, and prevention strategies. HCMV-induced hearing loss primarily involves immune responses, the release of inflammatory factors by natural killer (NK) cells, apoptosis of cochlear spiral ganglion, and potential changes due to vascular dysfunction. The diagnosis of HCMV induced SNHL includes serological examination to mothers, imaging, and amniotic fluid examination. Ganciclovir, mainly used for antiviral therapy and behavioral prevention, can, to some degree, prevent congenital HCMV infection. The role of HCMV infection in hearing loss needs further investigation since the mechanism of hearing loss caused by cytomegalovirus infection is not well understood. Although some advancement has been made in diagnosing and treating SNHL, more improvement is needed. A comprehensive understanding of cytomegalovirus's pathogenesis is of key importance for preventing, diagnosing, and treating SNHL.
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http://dx.doi.org/10.3389/fmicb.2021.649690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079719PMC
April 2021

MicroRNA-93 Blocks Signal Transducers and Activator of Transcription 3 to Reduce Neuronal Damage in Parkinson's Disease.

Neurochem Res 2021 Jul 26;46(7):1859-1868. Epub 2021 Apr 26.

Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

MicroRNA-93 (miR-93) is an oncogene that promotes tumor growth and angiogenesis. However, its role in Parkinson's disease (PD) remains unknown. This study aimed at investigating the role of miR-93 in PD and the molecular mechanisms involved. 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mouse model and lipopolysaccharide (LPS)-exposed BV2 cells were constructed. Real-time quantitative PCR was used to detect the mRNA expression of miR-93, iNOS, IL-6, IL-10, TNF-α and TGF-β1. Bioinformatics analysis and luciferase reporter assay were used to predict and confirm the interaction between miR-93 and STAT3. Flow cytometry was used to detect cell apoptosis. Western blotting was used to detect the protein expression of STAT3. Immunohistochemistry was used to analyze the Iba1-positive and TH positive cells. It was found that the expression of miR-93 was down-regulated in LPS-exposed BV2 cells. Overexpression of miR-93 inhibited the expression of iNOS, IL-6 and TNF-α, while enhanced the expression of TGF-β1 and IL-10. The expression of transcriptional activator 3 (STAT3) was found to be up-regulated in LPS-exposed BV2 cells. Knockdown of STAT3 inhibited the expression of iNOS, IL-6 and TNF-α, while enhanced the expression of TGF-β1 and IL-10. Moreover, STAT3 was found to be a direct target of miR-93, and miR-93 overexpression inhibited the expression of STAT3. Furthermore, both miR-93 overexpression and STAT3 knockdown reduced LPS-induced BV2 cell apoptosis, whereas STAT3 overexpression eliminated the inhibitory effect of miR-93 on LPS-induced BV2 cell apoptosis. In addition, miR-93 overexpression inhibited MPTP-induced STAT3 expression, microglial activation and inflammatory reaction and reduced the loss of tyrosine hydroxylase in the substantia nigra of mice. In conclusion, we demonstrate that miR-93 may be involved in PD by regulating the expression of STAT3.
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http://dx.doi.org/10.1007/s11064-021-03333-xDOI Listing
July 2021

Rapid, ultrasensitive and non-enzyme electrochemiluminescence detection of hydrogen peroxide in food based on the ssDNA/g-CN nanosheets hybrid.

Food Chem 2021 Apr 8;357:129753. Epub 2021 Apr 8.

School of the Environment, Jiangsu University, Zhenjiang 212013, China. Electronic address:

Hydrogen peroxide (HO) is usually used as a fungicide in food, it is carcinogenic, accelerates aging or inducing toxic effects such as cardiovascular disease. Herein, to meet the demand for effective and fast detection of HO in food, a novel non-enzymatic electrochemiluminescence (ECL) sensor based on single-stranded DNA (ssDNA)/g-CN nanosheets (NS) was established. The ssDNA/g-CN NS hybrid was prepared by simple mixing g-CN NS and ssDNA solution together. The prepared ssDNA/g-CN NS exhibited improved peroxidase-like activity and was modified on a glassy carbon electrode to catalyze the ECL reaction of luminol-HO to amplify the luminescence signal. Under the optimized conditions, the proposed sensor exhibits high sensitivity with a limit of detection (LOD) as low as 33 aM HO, which is much lower than the vast majority of reported methods. This method enables the reliable responding to HO from the milk samples within 1 min.
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http://dx.doi.org/10.1016/j.foodchem.2021.129753DOI Listing
April 2021

Osmolytes Can Destabilize Proteins in Cells by Modulating Electrostatics and Quinary Interactions.

ACS Chem Biol 2021 05 12;16(5):864-871. Epub 2021 Apr 12.

National Facility for Protein Science, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.

Although numerous studies have shown that osmolytes are capable of stabilizing proteins, their effect on protein folding has been less understood. In this work, we investigated the effect of osmolytes, including glycerol, sorbitol, betaine, and taurine, on the folding of a protein GB3 variant in cells using NMR spectroscopy. 400 mM osmolytes were added to cells; only glycerol stabilizes the folded protein, whereas betaine and taurine considerably destabilize the protein through modulating folding and unfolding rates. Further investigation indicates that betaine and taurine can enhance the quinary interaction between the protein and cellular environment and manifestly weaken the electrostatic attraction in protein salt bridges. The combination of the two factors causes destabilization of the protein in cells. These factors counteract the preferential exclusion mechanism that is adopted by osmolytes to stabilize proteins.
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http://dx.doi.org/10.1021/acschembio.1c00024DOI Listing
May 2021

Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Like Activity.

Molecules 2021 Mar 30;26(7). Epub 2021 Mar 30.

Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.

Aha1 is the only co-chaperone known to strongly stimulate the ATPase activity of Hsp90. Meanwhile, besides the well-studied co-chaperone function, human Aha1 has also been demonstrated to exhibit chaperoning activity against stress-denatured proteins. To provide structural insights for a better understanding of Aha1's co-chaperone and chaperone-like activities, nuclear magnetic resonance (NMR) techniques were used to reveal the unique structure and internal dynamics features of full-length human Aha1. We then found that, in solution, both the two domains of Aha1 presented distinctive thermal stabilities and dynamics behaviors defined by their primary sequences and three-dimensional structures. The low thermal stability (melting temperature of Aha1: 54.45 °C) and the internal dynamics featured with slow motions on the µs-ms time scale were detected for Aha1's N-terminal domain (Aha1N). The aforementioned experimental results suggest that Aha1N is in an energy-unfavorable state, which would therefore thermostatically favor the interaction of Aha1N with its partner proteins such as Hsp90's middle domain. Differently from Aha1N, Aha1C (Aha1's C-terminal domain) exhibited enhanced thermal stability (melting temperature of Aha1: 72.41 °C) and the internal dynamics featured with intermediate motions on the ps-ns time scale. Aha1C's thermal and structural stabilities make it competent for the stabilization of the exposed hydrophobic groove of dimerized Hsp90's N-terminal domain. Of note, according to the NMR data and the thermal shift results, although the very N-terminal region (M1-W27) and the C-terminal relaxin-like factor (RLF) motif showed no tight contacts with the remaining parts of human Aha1, they were identified to play important roles in the recognition of intrinsically disordered pathological α-synuclein.
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http://dx.doi.org/10.3390/molecules26071943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037086PMC
March 2021

Synergistic integration of dihydro-artemisinin with γ-aminobutyric acid results in a more potential anti-depressant.

Bioorg Chem 2021 May 25;110:104769. Epub 2021 Feb 25.

Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou 510632, PR China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, School of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address:

Three hybrids of dihydro-artemisinin (DHA) with β-aminopropionic acid, γ-aminobutyric acid, and histamine have been designed and synthesized. The conjugate of DHA with GABA labelled as 5b was confirmed the most active candidate against both Cort- and SNP-induced PC12 cell impairments with EC value of 8.04 ± 0.35, and 9.38 ± 0.56 μM, respectively. 5b was clearly highlighted as a good modulator on protein expression of Akt, Bcl-2, and Bax, indicating its functions against programmed cell apoptosis. 5b significantly reversed the Cort-induced excessive calcium influx and release from internal organelles. It was demonstrated the ability to express increased levels of β-tubulin III and to up-regulate phosphorylation level of cAMP response element-binding protein (CREB), leading to cell differentiation. It can penetrate blood - brain barrier (BBB) with propriate stability. Altogether, these data strongly support that 5b is a potential anti-depressant.
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http://dx.doi.org/10.1016/j.bioorg.2021.104769DOI Listing
May 2021

A stochastic epidemic model with infectivity in incubation period and homestead-isolation on the susceptible.

J Appl Math Comput 2021 Feb 15:1-21. Epub 2021 Feb 15.

School of Mathematics and Statistics, Hubei Minzu University, Enshi, 445000 Hubei People's Republic of China.

A stochastic epidemic model with infectivity rate in incubation period and homestead-isolation on the susceptible is developed with the aim of revealing the effect of stochastic white noise on the long time behavior. A good understanding of extinction and strong persistence in the mean of the disease is obtained. Also, we derive sufficient criteria for the existence of a unique ergodic stationary distribution of the model. Our theoretical results show that the suitably large noise can make the disease extinct while the relatively small noise is advantageous for persistence of the disease and stationary distribution.
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http://dx.doi.org/10.1007/s12190-021-01504-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882865PMC
February 2021

An application of a novel geometric criterion to global-stability problems of a nonlinear SEIVS epidemic model.

J Appl Math Comput 2021 Feb 8:1-24. Epub 2021 Feb 8.

School of Mathematics and Statistics, Hubei Minzu University, Enshi, 445000 People's Republic of China.

This work applies a novel geometric criterion for nonlinear autonomous differential equations developed by Lu and Lu (NARWA 36:20-43, 2017) to a nonlinear SEIVS epidemic model with temporary immunity and achieves its threshold dynamics. Specifically, global-stability problems for the SEIVS model of Cai and Li (AMM 33:2919-2926, 2009) are effectively solved. The corresponding optimal control system with vaccination, awareness campaigns and treatment is further established and four different control strategies are compared by numerical simulations to contain hepatitis B. It is concluded that joint implementation of these measures can minimize the numbers of exposed and infectious individuals in the shortest time, so it is the most efficient strategy to curb the hepatitis B epidemic. Moreover, vaccination for newborns plays the core role and maintains the high level of population immunity.
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http://dx.doi.org/10.1007/s12190-020-01487-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869433PMC
February 2021

Thermal adaptation of structural dynamics and regulatory function of adenine riboswitch.

RNA Biol 2021 Feb 25:1-9. Epub 2021 Feb 25.

State Key Laboratory of Microbial Metabolism, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Ligand binding and temperature play important roles in riboswitch RNAs' structures and functions. However, most studies focused on studying structural dynamics or gene-regulation function of riboswitches from the aspect of ligand, instead of temperature. Here we combined NMR, ITC, stopped-flow and assays to investigate the ligand-triggered switch of adenine riboswitch from 10 to 45°C. Our results demonstrated that at single-nucleotide resolution, structural regions sensed ligand and temperature diversely. Temperature had opposite effects on ligand-binding and gene-regulation of adenine riboswitch. Compared with higher temperature, the RNA bound with its cognate ligand obviously stronger, while its regulatory capacity was weakened at lower temperature. In addition, application of specific-labelled RNAs to the stopped-flow experiments identified the real-time folding of the specific positions upon ligand addition at different temperatures. The kissing loop and internal loop at the riboswitch responded to ligand and temperature differently. The distinct thermo-dynamics of adenine riboswitch exposed here may contribute to the fields of RNA sensors and drug design.
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http://dx.doi.org/10.1080/15476286.2021.1886755DOI Listing
February 2021

Convolutional Neural Network for Behavioral Modeling and Predistortion of Wideband Power Amplifiers.

IEEE Trans Neural Netw Learn Syst 2021 Feb 10;PP. Epub 2021 Feb 10.

Power amplifier (PA) models, such as the neural network (NN) models and the multilayer NN models, have problems with high complexity. In this article, we first propose a novel behavior model for wideband PAs, using a real-valued time-delay convolutional NN (RVTDCNN). The input data of the model is sorted and arranged as a graph composed of the in-phase and quadrature (I/Q) components and envelope-dependent terms of current and past signals. Then, we created a predesigned filter using the convolutional layer to extract the basis functions required for the PA forward or reverse modeling. Finally, the generated rich basis functions are input into a simple, fully connected layer to build the model. Due to the weight sharing characteristics of the convolutional model's structure, the strong memory effect does not lead to a significant increase in the complexity of the model. Meanwhile, the extraction effect of the predesigned filter also reduces the training complexity of the model. The experimental results show that the performance of the RVTDCNN model is almost the same as the NN models and the multilayer NN models. Meanwhile, compared with the abovementioned models, the coefficient number and computational complexity of the RVTDCNN model are significantly reduced. This advantage is noticeable when the memory effects of the PA are increased by using wider signal bandwidths.
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http://dx.doi.org/10.1109/TNNLS.2021.3054867DOI Listing
February 2021

The Role of Calcium in Regulating the Conformational Dynamics of d-Galactose/d-Glucose-Binding Protein Revealed by Markov State Model Analysis.

J Chem Inf Model 2021 Feb 14;61(2):891-900. Epub 2021 Jan 14.

Department of Chemistry, Multiscale Research Institute of Complex Systems and Institute of Biomedical Sciences, Fudan University, Shanghai 200438, China.

The d-glucose/d-galactose-binding protein (GGBP) from is a substrate-binding protein (SBP) associated with sugar transport and chemotaxis. It is also a calcium-binding protein, which makes it unique in the SBP family. However, the functional importance of Ca binding is not fully understood. Here, the calcium-dependent properties of GGBP were explored by all-atom molecular dynamics simulations and Markov state model (MSM) analysis as well as single-molecule Förster resonance energy transfer (smFRET) measurements. In agreement with previous experimental studies, we observed the structure stabilization effect of Ca binding on the C-terminal domain of GGBP, especially the Ca-binding site. Interestingly, the MSMs of calcium-depleted GGBP and calcium-bound GGBP (GGBP/Ca) demonstrate that Ca greatly stabilizes the open conformation, and smFRET measurements confirmed this result. Further analysis reveals that Ca binding disturbs the local hydrogen bonding interactions and the conformational dynamics of the hinge region, thereby weakening the long-range interdomain correlations to favor the open conformation. These results suggest an active regulatory role of Ca binding in GGBP, which finely tunes the conformational distribution. The work sheds new light on the study of calcium-binding proteins in prokaryotes.
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http://dx.doi.org/10.1021/acs.jcim.0c01119DOI Listing
February 2021

A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation.

Immunity 2021 Feb 13;54(2):247-258.e7. Epub 2021 Jan 13.

Department of Immunology, Duke University School of Medicine, DUMC 3010, Durham, NC 27710, USA; Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address:

The vaccine strain against smallpox, vaccinia virus (VACV), is highly immunogenic yet causes relatively benign disease. These attributes are believed to be caused by gene loss in VACV. Using a targeted small interfering RNA (siRNA) screen, we identified a viral inhibitor found in cowpox virus (CPXV) and other orthopoxviruses that bound to the host SKP1-Cullin1-F-box (SCF) machinery and the essential necroptosis kinase receptor interacting protein kinase 3 (RIPK3). This "viral inducer of RIPK3 degradation" (vIRD) triggered ubiquitination and proteasome-mediated degradation of RIPK3 and inhibited necroptosis. In contrast to orthopoxviruses, the distantly related leporipoxvirus myxoma virus (MYXV), which infects RIPK3-deficient hosts, lacks a functional vIRD. Introduction of vIRD into VACV, which encodes a truncated and defective vIRD, enhanced viral replication in mice. Deletion of vIRD reduced CPXV-induced inflammation, viral replication, and mortality, which were reversed in RIPK3- and MLKL-deficient mice. Hence, vIRD-RIPK3 drives pathogen-host evolution and regulates virus-induced inflammation and pathogenesis.
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http://dx.doi.org/10.1016/j.immuni.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878414PMC
February 2021

Leaf and Soil Eco-Stoichiometry in the Yancheng Coastal Wetland.

Plants (Basel) 2020 Dec 23;10(1). Epub 2020 Dec 23.

Institute of Wetland Research, Chinese Academy of Forestry, Beijing Key Laboratory of Wetland Ecological Function and Restoration, Beijing 100091, China.

Carbon, nitrogen, and phosphorus-nutrient and restrictive elements for plant growth and important components of the plant body-are mainly transferred and exchanged between plants and the soil environment. Changes in the carbon, nitrogen, and phosphorus eco-stoichiometry greatly impact the growth and expansion of , and understanding these changes can reveal the nutrient coordination mechanism among ecosystem components. To explore the relationship between leaf and soil eco-stoichiometry and determine the key soil factors that affect leaf eco-stoichiometry, we collected leaf and soil samples of at different tidal levels (i.e., 1, 3, and 5 km away from the coastline) in a coastal wetland in the Yancheng Elk Nature Reserve, Jiangsu province. We measured the leaf and soil carbon, nitrogen, and phosphorus contents and ratios, as well as the soil salinity and soil organic carbon. The results revealed the following. (1) The leaf stoichiometric characteristics and soil properties of differed significantly between tidal levels; for example, total carbon, nitrogen, soil organic carbon were detected at their highest levels at 3 km and lowest levels at 5 km. (2) Significant correlations were detected between the leaf stoichiometric characteristics and soil characteristics. Additionally, nitrogen limitation was evident in the study area, as indicated by the nitrogen-phosphorus ratio being less than 14 and the soil nitrogen-phosphorus ratio being less than 1. (3) Soil salinity and the soil carbon-nitrogen ratio were shown to be the key factors that affect the eco-stoichiometric characteristics of . These findings furthered our understanding of the nutrient distribution mechanisms and invasion strategy of and can thus be used to guide control policies formulated by government management departments in China.
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http://dx.doi.org/10.3390/plants10010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824427PMC
December 2020

RssB-mediated σ Activation is Regulated by a Two-Tier Mechanism via Phosphorylation and Adaptor Protein - IraD.

J Mol Biol 2021 02 18;433(3):166757. Epub 2020 Dec 18.

BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi 710061, China; Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ London, United Kingdom; Instrument Analysis Center of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China. Electronic address:

Regulation of bacterial stress responding σ is a sophisticated process and mediated by multiple interacting partners. Controlled proteolysis of σ is regulated by RssB which maintains minimal level of σ during exponential growth but then elevates σ level while facing stresses. Bacteria developed different strategies to regulate activity of RssB, including phosphorylation of itself and production of anti-adaptors. However, the function of phosphorylation is controversial and the mechanism of anti-adaptors preventing RssB-σ interaction remains elusive. Here, we demonstrated the impact of phosphorylation on the activity of RssB and built the RssB-σ complex model. Importantly, we showed that the phosphorylation site - D58 is at the interface of RssB-σ complex. Hence, mutation or phosphorylation of D58 would weaken the interaction of RssB with σ. We found that the anti-adaptor protein IraD has higher affinity than σ to RssB and its binding interface on RssB overlaps with that for σ. And IraD-RssB complex is preferred over RssB-σ in solution, regardless of the phosphorylation state of RssB. Our study suggests that RssB possesses a two-tier mechanism for regulating σ. First, phosphorylation of RssB provides a moderate and reversible tempering of its activity, followed by a specific and robust inhibition via the anti-adaptor interaction.
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http://dx.doi.org/10.1016/j.jmb.2020.166757DOI Listing
February 2021

Conjugation of tacrine with genipin derivative not only enhances effects on AChE but also leads to autophagy against Alzheimer's disease.

Eur J Med Chem 2021 Feb 2;211:113067. Epub 2020 Dec 2.

Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou, 510632, PR China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, School of Pharmacy, Jinan University, Guangzhou, 510632, PR China. Electronic address:

Seven tacrine/CHR21 conjugates have been designed and synthesized. Compound 8-7 was confirmed as the most active AChE inhibitor with IC value of 5.8 ± 1.4 nM, which was 7.72-fold stronger than tacrine. It was also shown as a strong BuChE inhibitor (IC value of 3.7 ± 1.3 nM). 8-7 was clearly highlighted not only as an excellent ChEs inhibitor, but also as a good modulator on protein expression of AChE, p53, Bax, Bcl-2, LC3, p62, and ULK, indicating its functions against programmed cell apoptosis and decrease of autophagy. 8-7 significantly reversed the glutamate-induced dysfunctions including excessive calcium influx and release from internal organelles, overproduction of nitric oxide (NO) and Aβ high molecular weight oligomer. This compound can penetrate blood-brain barrier (BBB). The in vivo hepatotoxicity assay indicated that 8-7 was much less toxic than tacrine. Altogether, these data strongly support that 8-7 is a potential multitarget-directed ligand (MTDL) for treating Alzheimer's disease (AD).
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http://dx.doi.org/10.1016/j.ejmech.2020.113067DOI Listing
February 2021

Novel risk scoring system for predicting acute respiratory distress syndrome among hospitalized patients with coronavirus disease 2019 in Wuhan, China.

BMC Infect Dis 2020 Dec 17;20(1):960. Epub 2020 Dec 17.

Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical Collage, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China.

Background: The mortality rate from acute respiratory distress syndrome (ARDS) is high among hospitalized patients with coronavirus disease 2019 (COVID-19). Hence, risk evaluation tools are required to immediately identify high-risk patients upon admission for early intervention.

Methods: A cohort of 220 consecutive patients with COVID-19 were included in this study. To analyze the risk factors of ARDS, data obtained from approximately 70% of the participants were randomly selected and used as training dataset to establish a logistic regression model. Meanwhile, data obtained from the remaining 30% of the participants were used as test dataset to validate the effect of the model.

Results: Lactate dehydrogenase, blood urea nitrogen, D-dimer, procalcitonin, and ferritin levels were included in the risk score system and were assigned a score of 25, 15, 34, 20, and 24, respectively. The cutoff value for the total score was > 35, with a sensitivity of 100.00% and specificity of 81.20%. The area under the receiver operating characteristic curve and the Hosmer-Lemeshow test were 0.967 (95% confidence interval [CI]: 0.925-0.989) and 0.437(P Value = 0.437). The model had excellent discrimination and calibration during internal validation.

Conclusions: The novel risk score may be a valuable risk evaluation tool for screening patients with COVID-19 who are at high risk of ARDS.
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http://dx.doi.org/10.1186/s12879-020-05561-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744733PMC
December 2020

Toll-like receptor-mediated innate immunity against herpesviridae infection: a current perspective on viral infection signaling pathways.

Virol J 2020 12 9;17(1):192. Epub 2020 Dec 9.

Department of Medical Microbiology, School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China.

Background: In the past decades, researchers have demonstrated the critical role of Toll-like receptors (TLRs) in the innate immune system. They recognize viral components and trigger immune signal cascades to subsequently promote the activation of the immune system.

Main Body: Herpesviridae family members trigger TLRs to elicit cytokines in the process of infection to activate antiviral innate immune responses in host cells. This review aims to clarify the role of TLRs in the innate immunity defense against herpesviridae, and systematically describes the processes of TLR actions and herpesviridae recognition as well as the signal transduction pathways involved.

Conclusions: Future studies of the interactions between TLRs and herpesviridae infections, especially the subsequent signaling pathways, will not only contribute to the planning of effective antiviral therapies but also provide new molecular targets for the development of antiviral drugs.
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http://dx.doi.org/10.1186/s12985-020-01463-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726878PMC
December 2020

Dynamic folding modulation generates FGF21 variant against diabetes.

EMBO Rep 2021 01 9;22(1):e51352. Epub 2020 Dec 9.

High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.

Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21-based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of FGF21 and find that its non-canonical flexible β-trefoil conformation affects the folding of β2-β3 hairpin and further overall protein stability. To modulate folding dynamics, we designed an FGF21-FGF19 chimera, FGF21 . As expected, FGF21 shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21 shows its better insulin sensitivity, reduced inflammation in 3T3-L1 adipocytes, and lower blood glucose and insulin levels in ob/ob mice compared with wild type. Our dynamics-based rational design provides a promising approach for FGF21-based therapeutic development against T2DM.
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http://dx.doi.org/10.15252/embr.202051352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788455PMC
January 2021

Hsp40 proteins phase separate to chaperone the assembly and maintenance of membraneless organelles.

Proc Natl Acad Sci U S A 2020 12 23;117(49):31123-31133. Epub 2020 Nov 23.

Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China;

Membraneless organelles contain a wide spectrum of molecular chaperones, indicating their important roles in modulating the metastable conformation and biological function of membraneless organelles. Here we report that class I and II Hsp40 (DNAJ) proteins possess a high ability of phase separation rendered by the flexible G/F-rich region. Different Hsp40 proteins localize in different membraneless organelles. Specifically, human Hdj1 (DNAJB1), a class II Hsp40 protein, condenses in ubiquitin (Ub)-rich nuclear bodies, while Hdj2 (DNAJA1), a class I Hsp40 protein, condenses in nucleoli. Upon stress, both Hsp40 proteins incorporate into stress granules (SGs). Mutations of the G/F-rich region not only markedly impaired Hdj1 phase separation and SG involvement and disrupted the synergistic phase separation and colocalization of Hdj1 and fused in sarcoma (FUS) in cells. Being cophase separated with FUS, Hdj1 stabilized the liquid phase of FUS against proceeding into amyloid aggregation in vitro and alleviated abnormal FUS aggregation in cells. Moreover, Hdj1 uses different domains to chaperone FUS phase separation and amyloid aggregation. This paper suggests that phase separation is an intrinsic property of Hsp40 proteins, which enables efficient incorporation and function of Hsp40 in membraneless organelles and may further mediate the buildup of chaperone network in membraneless organelles.
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http://dx.doi.org/10.1073/pnas.2002437117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733851PMC
December 2020

Simple Tripedal DNA Walker Prepared by Target-Triggered Catalytic Hairpin Assembly for Ultrasensitive Electrochemiluminescence Detection of MicroRNA.

ACS Sens 2020 11 10;5(11):3584-3590. Epub 2020 Nov 10.

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

In contrast to common DNA walkers, multipedal DNA walkers exhibit larger walking area and faster walking kinetics and provide increased amplification efficiency. Consequently, they have received a considerable amount of attention in biosensing. However, most of them are synthesized by immobilizing multiple DNA walking strands on the surface of Au nanoparticles, which is tedious and time-consuming. Simple preparation of multipedal DNA walkers remains a challenge. Herein, we adopted a simple enzyme-free target-triggered catalytic hairpin assembly (CHA) circuit to synthesize a tripedal DNA walker. By walking on a DNA track-functionalized electrode, a sensitive electrochemiluminescence DNA nanomachine biosensor was constructed for sensing miRNA-21. The DNA walker was powered by toehold-mediated strand displacement; the whole process did not need the assistance of enzymes, thus avoiding tedious procedures and enzyme degradation under unfavorable environmental conditions. Specifically, a superior detection limit of 4 aM and a broad linear range of 10 aM to 1 pM were achieved. This CHA-tripedal DNA walker biosensor was then applied for the detection of miRNA-21 in human serum and showed high selectivity and excellent reproducibility, demonstrating its practical application in bioanalysis. In particular, the Y-shaped tripedal DNA walker comes from the DNA circuit, which makes the approach ideally suited for biosensing of small nucleic acid targets.
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http://dx.doi.org/10.1021/acssensors.0c01864DOI Listing
November 2020

LncRNA BANCR induced vascular smooth muscle cell proliferation by downregulating miR-34c methylation in atherosclerosis.

J Thromb Thrombolysis 2021 May 5;51(4):924-932. Epub 2020 Nov 5.

Department of Cardiology, Cardio Cerebrovascular Disease Branch of General Hospital of Ningxia Medical University, No. 6 Ning'an East Lane, Jinfeng District, Yinchuan, Ningxia Province, 750004, China.

Aberrant vascular smooth muscle cell (VSMCs) proliferation involves in the development of atherosclerosis. It reported that Long noncoding BRAF-activated noncoding RNA (BANCR) and miR-34c played opposite roles in the regulation of the proliferation of VSMCs, indicating that there might be a potential interaction between them. This study was to investigate the relationship between BANCR and miR-34c in atherosclerosis. Blood (5 ml) was obtained from 56 patients with atherosclerosis and 56 healthy volunteers after they were fasted overnight, and plasma was extracted from the blood. Human Aortic Smooth Muscle Cells (HASMCs) were used to perform in vitro cell experiments. RT-qPCR was performed to measure the expression of BANCR and miR-34c in plasma and HASMCs. Dual luciferase reporter assay detected the interaction between BANCR and miR-34c. CCK-8 assay was used to assess the effects of BANCR and miR-34c overexpression on the proliferation of HASMCs. Western blotting was used to assess the effects of BANCR and miR-34c overexpression on the protein expression of HMGB1, TNF-ɑ and Bcl-2. In this study, we found that BANCR was upregulated, while miR-34c was downregulated in atherosclerosis. Bioinformatics analysis showed that BANCR and miR-34c could directly interact with each other. Moreover, overexpression of BANCR could decrease the expression of miR-34c in HASMCs, but overexpression of miR-34c could not affect the expression of BANCR. Furthermore, overexpression of BACNR increased miR-34c methylation, and knockdown of endogenous BANCR decreased miR-34c methylation. In addition, overexpression of BANCR reduced the effects of miR-34c on HASMCs proliferation and reversed the effects of miR-34c on HMGB1, TNF-ɑ and Bcl-2 expression. BANCR overexpression could induce HASMCs proliferation by downregulating the miR-34c methylation. Therefore given BANCR upregulation in atherosclerosis, its expression may be considered as a novel and useful biomarker for atherosclerosis prevention and prognosis. However considering the possible effects of other underlying diseases on both BANCR expression and miR-34c in atherosclerosis, further investigation is suggested for future research.
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http://dx.doi.org/10.1007/s11239-020-02314-1DOI Listing
May 2021

Generalized inverse matrix normalization algorithm to extract high-temperature data from multiwavelength pyrometry.

Rev Sci Instrum 2020 Oct;91(10):104903

College of Mechanical and Electrical Engineering, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China.

Multiwavelength pyrometry (MWP) is one of the most powerful tools for the precise measurement of high temperatures on the surfaces of non-gray materials. However, the unknown spectral emissivity of target materials is the most difficult obstacle to overcome in processing temperature inversion data using MWP. A direct and fast generalized inverse matrix normalization (GIM-NOR) data processing algorithm based on GIM theory for underdetermined equations is proposed in order to minimize the effects arising from unknown emissivity. The shape of the emissivity distribution is obtained so that the channel with the greatest emissivity can be selected in order to obtain a value close to the real temperature. The final inversion accuracy is then further improved using a NOR compensation method. Six kinds of materials with a distribution of emissivities at 1800 K were used to simulate and verify the proposed algorithm. The results show that the average relative error of temperature inversion was 0.63%, obtained within 8 ms computation time using a standard desktop computer, and the accuracy and efficiency were largely unaffected when 5% random noise was inserted into the simulation data. A set of experimental data for rocket nozzle temperature measurements with MWP were also processed based on the proposed novel algorithm. The results show that the relative error on the temperature was less than 0.50%, for a design temperature of 2490 K, and that the processing efficiency was very high, that is, within 9 ms. Simulation and experiment both proved that the proposed efficient data processing algorithm for MWP based on GIM theory was unaffected by emissivity and achieved good inversion precision and fast data processing. Therefore, the proposed new data processing algorithm for MWP data for measuring transient high temperatures has very broad potential applications, and it also provides a theoretical basis for measuring high-temperature fields using MWP.
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http://dx.doi.org/10.1063/5.0016747DOI Listing
October 2020

Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression.

Nat Commun 2020 10 27;11(1):5424. Epub 2020 Oct 27.

Division of Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA.

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.
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http://dx.doi.org/10.1038/s41467-020-19193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591536PMC
October 2020