Publications by authors named "Kai Xue"

170 Publications

Recent Developments in Data-Assisted Modeling of Flexible Proteins.

Front Mol Biosci 2021 24;8:765562. Epub 2021 Dec 24.

Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland.

Many proteins can fold into well-defined conformations. However, intrinsically-disordered proteins (IDPs) do not possess a defined structure. Moreover, folded multi-domain proteins often digress into alternative conformations. Collectively, the conformational dynamics enables these proteins to fulfill specific functions. Thus, most experimental observables are averaged over the conformations that constitute an ensemble. In this article, we review the recent developments in the concept and methods for the determination of the dynamic structures of flexible peptides and proteins. In particular, we describe ways to extract information from nuclear magnetic resonance small-angle X-ray scattering (SAXS), and chemical cross-linking coupled with mass spectroscopy (XL-MS) measurements. All these techniques can be used to obtain ensemble-averaged restraints or to re-weight the simulated conformational ensembles.
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http://dx.doi.org/10.3389/fmolb.2021.765562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740120PMC
December 2021

Backbone Torsion Angle Determination Using Proton Detected Magic-Angle Spinning Nuclear Magnetic Resonance.

J Phys Chem Lett 2022 Jan 27;13(1):18-24. Epub 2021 Dec 27.

Max Planck Institute for Biophysical Chemistry, Department of NMR Based Structural Biology, Am Fassberg. 11, 37077 Goettingen, Germany.

Protein torsion angles define the backbone secondary structure of proteins. Magic-angle spinning (MAS) NMR methods using carbon detection have been developed to measure torsion angles by determining the relative orientation between two anisotropic interactions─dipolar coupling or chemical shift anisotropy. Here we report a new proton-detection based method to determine the backbone torsion angle by recoupling NH and CH dipolar couplings within the HCANH pulse sequence, for protonated or partly deuterated samples. We demonstrate the efficiency and precision of the method with microcrystalline chicken α spectrin SH3 protein and the influenza A matrix 2 (M2) membrane protein, using 55 or 90 kHz MAS. For M2, pseudo-4D data detect a turn between transmembrane and amphipathic helices.
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http://dx.doi.org/10.1021/acs.jpclett.1c03267DOI Listing
January 2022

Anaerobic methane oxidation linked to Fe(III) reduction in a Candidatus Methanoperedens-enriched consortium from the cold Zoige wetland at Tibetan Plateau.

Environ Microbiol 2021 Dec 23. Epub 2021 Dec 23.

University of Chinese Academy of Sciences, No.19A Yuquan Road, Shijingshan District, Beijing, 100049, China.

Anaerobic oxidation of methane (AOM) is a microbial process degrading ample methane in anoxic environments, and Ca. Methanoperedens mediated nitrate- or metal-reduction linked AOM is believed important in freshwater systems. This work, via 16S rRNA gene diversity survey and 16S rRNA quantification, found abundant Ca. Methanoperedens along with iron in the cold Zoige wetland at Tibetan Plateau. The wetland soil microcosm performed Fe(III) reduction, rather than nitrate- nor sulphate-reduction, coupled methane oxidation (3.87 μmol d ) with 32.33 μmol Fe(II) accumulation per day at 18°C, but not at 30°C. A metagenome-assembled genome (MAG) recovered from the microcosm exhibits ~74% average nucleotide identity with the reported Ca. Methanoperedens spp. that perform Fe(III) reduction linked AOM, thus a novel species Ca. Methanoperedens psychrophilus was proposed. Ca. M. psychrophilus contains the whole suite of CO reductive methanogenic genes presumably involving in AOM via a reverse direction, and comparative genome analysis revealed its unique gene categories: the multi-heme clusters (MHCs) cytochromes, the S-layer proteins highly homologous to those recovered from lower temperature environments and type IV pili, those could confer Ca. M. psychrophilus of cold adaptability. Therefore, this work reports the first methanotroph implementing AOM in an alpine wetland.
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http://dx.doi.org/10.1111/1462-2920.15848DOI Listing
December 2021

Immune-relatedlncRNAs can predict the prognosis of acute myeloid leukemia.

Cancer Med 2021 Dec 14. Epub 2021 Dec 14.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The immune microenvironment in acute myeloid leukemia (AML) is closely related to patients' prognosis. Long noncoding RNAs (lncRNAs) are emerging as key regulators in immune systems. In this study, we established a prognostic model using an immune-related lncRNA (IRL) signature to predict AML patients' overall survival (OS) through Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate Cox regression analysis. Kaplan-Meier analysis, receiver operating characteristic (ROC) analysis, univariate Cox regression, and multivariate Cox regression analyses further illustrated the reliability of our prognostic model. An IRL signature-based nomogram consisting of other clinical features efficiently predicted the OS of AML patients. The incorporation of the IRL signature improved the ELN2017 risk stratification system's prognostic accuracy. In addition, we found that monocytes and metabolism-related pathways may play a role in AML progression. Overall, the IRL signature appears as a novel effective model for evaluating the OS of AML patients and may be implemented to contribute to the prolonged OS in AML patients.
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http://dx.doi.org/10.1002/cam4.4487DOI Listing
December 2021

Towards a native environment: structure and function of membrane proteins in lipid bilayers by NMR.

Chem Sci 2021 Nov 7;12(43):14332-14342. Epub 2021 Sep 7.

Max Planck Institute for Biophysical Chemistry, Department of NMR Based Structural Biology Am Fassberg. 11 Goettingen Germany

Solid-state NMR (ssNMR) is a versatile technique that can be used for the characterization of various materials, ranging from small molecules to biological samples, including membrane proteins. ssNMR can probe both the structure and dynamics of membrane proteins, revealing protein function in a near-native lipid bilayer environment. The main limitation of the method is spectral resolution and sensitivity, however recent developments in ssNMR hardware, including the commercialization of 28 T magnets (1.2 GHz proton frequency) and ultrafast MAS spinning (<100 kHz) promise to accelerate acquisition, while reducing sample requirement, both of which are critical to membrane protein studies. Here, we review recent advances in ssNMR methodology used for structure determination of membrane proteins in native and mimetic environments, as well as the study of protein functions such as protein dynamics, and interactions with ligands, lipids and cholesterol.
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http://dx.doi.org/10.1039/d1sc02813hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580007PMC
November 2021

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor-Mediated Intrarenal Renin-Angiotensin System and Nox4-HO Signaling.

Oxid Med Cell Longev 2021 26;2021:5710440. Epub 2021 Nov 26.

Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, 261053 Shandong, China.

Full-length (pro)renin receptor (fPRR), a research hotspot of the renin-angiotensin system (RAS), plays a serious role in kidney injury. However, the relationship between fPRR and advanced oxidation protein product (AOPP) remains largely unexplored. This study was aimed at exploring the effect of fPRR, especially its 28 kDa soluble form called soluble PRR (sPRR), in AOPP-induced oxidative stress in HK-2 cells, a renal proximal tubular epithelial cell line. Incubation of HK-2 cells with 100 g/ml AOPP resulted in significant upregulation of fPRR expression and caused an approximately fourfold increase in medium sPRR secretion. However, unmodified albumin did not demonstrate the same effects under the same concentration. Treatment of HK-2 cells with the site-1 protease (S1P) inhibitor PF429242 (40 M) or S1P siRNA significantly inhibited AOPP-induced sPRR generation. fPRR decoy inhibitor PRO20 and PF429242 treatment for 24 h remarkably attenuated the AOPP-induced upregulation of RAS components. Furthermore, PF429242 significantly reduced the AOPP-stimulated expression of NADPH oxidase 4 (Nox4) and HO expression. The use of a small recombinant protein, named sPRR-His, reversed these alterations. In conclusion, these results provided the first demonstration of AOPP-promoted activation of sPRR. Increased renal proximal tubule Nox4-derived HO contributed to the aggravation of oxidative stress. Targeting S1P-derived sPRR is a promising intervention strategy for chronic kidney disease.
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http://dx.doi.org/10.1155/2021/5710440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642821PMC
November 2021

Amantadine has potential for the treatment of COVID-19 because it inhibits known and novel ion channels encoded by SARS-CoV-2.

Commun Biol 2021 12 1;4(1):1347. Epub 2021 Dec 1.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The dire need for COVID-19 treatments has inspired strategies of repurposing approved drugs. Amantadine has been suggested as a candidate, and cellular as well as clinical studies have indicated beneficial effects of this drug. We demonstrate that amantadine and hexamethylene-amiloride (HMA), but not rimantadine, block the ion channel activity of Protein E from SARS-CoV-2, a conserved viroporin among coronaviruses. These findings agree with their binding to Protein E as evaluated by solution NMR and molecular dynamics simulations. Moreover, we identify two novel viroporins of SARS-CoV-2; ORF7b and ORF10, by showing ion channel activity in a X. laevis oocyte expression system. Notably, amantadine also blocks the ion channel activity of ORF10, thereby providing two ion channel targets in SARS-CoV-2 for amantadine treatment in COVID-19 patients. A screen of known viroporin inhibitors on Protein E, ORF7b, ORF10 and Protein 3a from SARS-CoV-2 revealed inhibition of Protein E and ORF7b by emodin and xanthene, the latter also blocking Protein 3a. This illustrates a general potential of well-known ion channel blockers against SARS-CoV-2 and specifically a dual molecular basis for the promising effects of amantadine in COVID-19 treatment. We therefore propose amantadine as a novel, cheap, readily available and effective way to treat COVID-19.
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http://dx.doi.org/10.1038/s42003-021-02866-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636635PMC
December 2021

Dysregulated MDR1 by PRDM1/Blimp1 Is Involved in the Doxorubicin Resistance of Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma.

Chemotherapy 2021 Nov 29:1-12. Epub 2021 Nov 29.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Introduction: The chemoresistance mechanism of diffuse large B-cell lymphoma (DLBCL) is still poorly understood, and patient prognosis remains unsatisfactory. This study aimed to investigate drug resistance mechanisms in non-germinal center B-cell-like (non-GCB) DLBCL.

Methods: Doxorubicin (DOX)-resistant OCI-Ly3 cells were generated through long-term incubation of cells in a medium with gradually increasing DOX concentrations. The expression levels of genes related to drug metabolism were determined using a functional gene grouping polymerase chain reaction (PCR) array. Drug-resistant proteins were identified using bioinformatics, and molecular association networks were subsequently generated. The association and mechanism of key genes were determined using a dual-luciferase reporter assay System and chromatin immunoprecipitation (ChIP). The expression of drug-resistant genes and target genes was then measured using Western blotting and immunohistochemistry. The correlation between gene expressions was analyzed using Spearman's rank correlation coefficient.

Results: Using the PCR array, MDR1 was identified as the key gene that regulates DOX resistance in OCI-Ly3/DOX-A100, a non-GCB DLBCL cell line. The dual-luciferase reporter assay system demonstrated that MDR1 transcription could be inhibited by PRDM1. ChIP results showed that PRDM1 had the ability to bind to the promoter region (-1,132 to -996) of MDR1. In OCI-Ly3/DOX cells, NF-κB activity and PRDM1 expression decreased with an increase in drug-resistant index, whereas MDR1 expression increased with enhanced drug resistance. Immunohistochemical analysis revealed that relative MDR1 expression was higher than that of PRDM1 in human DLBCL tissue samples. A negative correlation was observed between MDR1 and PRDM1.

Conclusion: In non-GCB DLBCL cells, NF-κB downregulates PRDM1 and thereby promotes MDR1 transcription by terminating PRDM1-induced transcriptional inhibition of MDR1. Such a mechanism may explain the reason for disease recurrence in non-GCB DLBCL after R-CHOP or combined CHOP with bortezomib treatment. Our findings may provide a potential therapeutic strategy for reducing drug resistance in patients with DLBCL.
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http://dx.doi.org/10.1159/000520070DOI Listing
November 2021

Three-Dimensional Solution for the Vibration Analysis of Functionally Graded Rectangular Plate with/without Cutouts Subject to General Boundary Conditions.

Materials (Basel) 2021 Nov 22;14(22). Epub 2021 Nov 22.

College of Mechanical and Electrical Engineering, Harbin Engineering University, Harbin 150001, China.

Functionally graded materials (FGMs) structures are increasingly used in engineering due to their superior mechanical and material properties, and the FGMs plate with cutouts is a common structural form, but research on the vibration characteristics of FGMs plate with cutouts is relatively limited. In this paper, the three-dimensional exact solution for the vibration analysis of FGMs rectangular plate with circular cutouts subjected to general boundary conditions is presented based on the three-dimensional elasticity theory. The displacement field functions are expressed as standard cosine Fourier series plus auxiliary cosine series terms satisfying the boundary conditions in the global coordinate system. The plate with circular cutout is discretized into four curve quadrilateral sub-domains using the -version method, and then the blending function method is applied to map the closed quadrilateral region to the computational space. The characteristic equation is obtained based on the Lagrangian energy principle and Rayleigh-Ritz method. The efficiency and reliability of proposed method are verified by comparing the present results with those available in the literature and FEM methods. Finally, a parametric study is investigated including the cutout sizes, the cutout positions, and the cutout numbers from the free vibration characteristic analysis and the harmonic analysis. The results can serve as benchmark data for other research on the vibration of FGMs plates with cutouts.
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http://dx.doi.org/10.3390/ma14227088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623222PMC
November 2021

Selective and competitive functions of the AAR and UPR pathways in stress-induced angiogenesis.

Cell Discov 2021 Oct 26;7(1):98. Epub 2021 Oct 26.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The amino acid response (AAR) and unfolded protein response (UPR) pathways converge on eIF2α phosphorylation, which is catalyzed by Gcn2 and Perk, respectively, under different stresses. This close interconnection makes it difficult to specify different functions of AAR and UPR. Here, we generated a zebrafish model in which loss of threonyl-tRNA synthetase (Tars) induces angiogenesis dependent on Tars aminoacylation activity. Comparative transcriptome analysis of the tars-mutant and wild-type embryos with/without Gcn2- or Perk-inhibition reveals that only Gcn2-mediated AAR is activated in the tars-mutants, whereas Perk functions predominantly in normal development. Mechanistic analysis shows that, while a considerable amount of eIF2α is normally phosphorylated by Perk, the loss of Tars causes an accumulation of uncharged tRNA, which in turn activates Gcn2, leading to phosphorylation of an extra amount of eIF2α. The partial switchover of kinases for eIF2α largely overwhelms the functions of Perk in normal development. Interestingly, although inhibition of Gcn2 and Perk in this stress condition both can reduce the eIF2α phosphorylation levels, their functional consequences in the regulation of target genes and in the rescue of the angiogenic phenotypes are dramatically different. Indeed, genetic and pharmacological manipulations of these pathways validate that the Gcn2-mediated AAR, but not the Perk-mediated UPR, is required for tars-deficiency induced angiogenesis. Thus, the interconnected AAR and UPR pathways differentially regulate angiogenesis through selective functions and mutual competitions, reflecting the specificity and efficiency of multiple stress response pathways that evolve integrally to enable an organism to sense/respond precisely to various types of stresses.
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http://dx.doi.org/10.1038/s41421-021-00332-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547220PMC
October 2021

Evenness is important in assessing progress towards sustainable development goals.

Natl Sci Rev 2021 Aug 28;8(8):nwaa238. Epub 2020 Sep 28.

College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.

Sustainable development goals (SDGs) emphasize a holistic achievement instead of cherry-picking a few. However, no assessment has quantitatively considered the evenness among all 17 goals. Here, we propose a systematic method, which first integrates both the evenness and the overall status of all goals, to distinguish the ideal development pathways from the uneven ones and then revisit the development trajectory in China from 2000 to 2015. Our results suggest that, despite the remarkable progress, a bottleneck has occurred in China since 2013 due to the stagnant developments in some SDGs. However, many far-reaching policies in China have been targeting these deficiencies since then, providing a perspective on how a country approaches sustainable development by promoting evenness among all SDGs. Our results also indicate that regions with the slowest progress are the developed provinces, owing to the persistent uneven status of all goals. Our study demonstrates the importance of adopting evenness in assessing and guiding sustainable development.
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http://dx.doi.org/10.1093/nsr/nwaa238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363329PMC
August 2021

Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma.

Cell Death Dis 2021 10 1;12(10):900. Epub 2021 Oct 1.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.
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http://dx.doi.org/10.1038/s41419-021-04187-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486747PMC
October 2021

Self-supporting dual-confined porous [email protected]@carbon nanofibers for high-performance lithium-ion batteries.

Chem Commun (Camb) 2021 Oct 12;57(81):10580-10583. Epub 2021 Oct 12.

School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212003, China.

Dual-confined porous [email protected]@carbon nanofibers ([email protected]@CNFs) are fabricated that possess excellent antioxidant capacity, high surface area and abundant pores, which enhances conductivity, relieves volume expansion and facilitates electrolyte penetration during cycling. When evaluated as self-supporting anodes for lithium-ion batteries, the [email protected]@CNFs exhibit excellent cycling and rate performance.
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http://dx.doi.org/10.1039/d1cc04172jDOI Listing
October 2021

Examining the robustness of the relationship between metacognitive efficiency and metacognitive bias.

Conscious Cogn 2021 10 1;95:103196. Epub 2021 Sep 1.

School of Psychology, Georgia Institute of Technology, Atlanta, GA, United States.

We recently found a positive relationship between estimates of metacognitive efficiency and metacognitive bias. However, this relationship was only examined on a within-subject level and required binarizing the confidence scale, a technique that introduces methodological difficulties. Here we examined the robustness of the positive relationship between estimates of metacognitive efficiency and metacognitive bias by conducting two different types of analyses. First, we developed a new within-subject analysis technique where the original n-point confidence scale is transformed into two different (n-1)-point scales in a way that mimics a naturalistic change in confidence. Second, we examined the across-subject correlation between metacognitive efficiency and metacognitive bias. Importantly, for both types of analyses, we not only established the direction of the effect but also computed effect sizes. We applied both techniques to the data from three tasks from the Confidence Database (N > 400 in each). We found that both approaches revealed a small to medium positive relationship between metacognitive efficiency and metacognitive bias. These results demonstrate that the positive relationship between metacognitive efficiency and metacognitive bias is robust across several analysis techniques and datasets, and have important implications for future research.
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http://dx.doi.org/10.1016/j.concog.2021.103196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560567PMC
October 2021

Elevated reactivity of Apelin inhibited renal fibrosis induced by chronic intermittent hypoxia.

Arch Biochem Biophys 2021 10 28;711:109021. Epub 2021 Aug 28.

Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, 261053, Shandong, China. Electronic address:

Background: Apelin and its receptor angiotensin receptor - like 1 (APJ) are closely related to renal fibrosis, but their specific roles in renal fibrosis are still controversial. In this article, we discussed the role of Apelin/APJ system in renal fibrosis and its mechanism.

Methods: Chronic intermittent hypoxia (CIH) rat model was established to induce the environment of renal fibrosis and a competitive antagonist of the APJ receptor ML221 was administered to CIH rats. The rats were divided into Control, CIH and ML221 groups. HE staining was used to detect the inflammatory injury and fibrosis of renal tissue. The expressions of renal fibrosis-related indicators transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and Human type I collagen (Col-Ⅰ) were detected by immunohistochemistry. The levels of oxidative stress indexes reactive oxygen species (ROS), Malondialdehyde (MDA), Superoxide Dismutase (SOD) and inflammation-related indexes Interleukin (IL) -6, tumor necrosis factor-α (TNF-α) and IL-1β were detected by ELISA. At the same time, the levels of Apelin-13 and AngiotensinII (AngⅡ) were also measured by ELISA. Finally, western blot was used to detect the expression of Apelin pathway and renal fibrosis-related proteins. In addition, at the cellular level, we divided the cells into Control, CIH, Apelin-13 and Apelin-13+ML-221 groups to further verify the specific mechanisms at the cellular level.

Results: The expression of Apeline-13 and its related pathways was significantly increased after the induction of CIH in rats. However, the degree of renal fibrosis in ML221 group was further significantly increased after inhibiting the expression of Apelin. At the cellular level, CIH model cells treated with Apelin-13 significantly reduced cell proliferation, oxidative stress and inflammatory response, and decreased the expression of fibrosis-related proteins, which can be reversed by ML221 administration.

Conclusion: The increased reactivity of Apelin may be one of the protective mechanisms against renal fibrosis induced by CIH.
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http://dx.doi.org/10.1016/j.abb.2021.109021DOI Listing
October 2021

KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2.

Blood Adv 2021 09;5(17):3241-3253

Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; and.

Epigenetic abnormalities are frequently involved in the initiation and progression of cancers, including acute myeloid leukemia (AML). A subtype of AML, acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of promyelocytic leukemia-RA receptor fusion oncoprotein (PML-RARα). PML-RARα was reported as a transcription repressor through the interaction with nuclear receptor corepressor and histone deacetylase complexes leading to the mis-suppression of its target genes and differentiation blockage. Although previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri-methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, KDM5A binding was detected in 1889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes, primarily by controlling the H3K4me2 in the promoters and 5' end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455, on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to all-trans retinoic acid-induced differentiation. Our findings indicate that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.
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http://dx.doi.org/10.1182/bloodadvances.2020002819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525237PMC
September 2021

Phase II study of sequential chemoradiotherapy with L-asparaginase, dexamethasone, ifosfamide, cisplatin, and etoposide (DICE-L) in the early stage of extranodal natural killer (NK)/T-cell lymphoma.

Ann Transl Med 2021 Jul;9(14):1178

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: To explore a more effective treatment strategy for newly diagnosed stage I and II extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, we conducted a prospective phase II study of sequential chemoradiotherapy with the L-asparaginase, dexamethasone, ifosfamide, cisplatin, and etoposide (DICE-L) regimen.

Methods: Patients with newly diagnosed stage I and II ENKTL in the upper-aerodigestive tract were enrolled. Treatment was comprised of up to 4 cycles of DICE-L followed by 50 Gy of intensity modulated radiation therapy (IMRT) to the involved field. The primary endpoint was the complete response (CR) rate. The secondary endpoints were the objective response rate (ORR), the 5-year overall survival (OS) rate, the 5-year progression-free survival (PFS) rate, and safety.

Results: A total of 81 patients were enrolled from June 2009 to May 2012 in Shanghai Cancer Hospital. Among these patients, 68 patients achieved CR and 1 patient achieved partial response (PR). The CR rate was 84%, and the ORR was 85.2%. With a median follow up of 88.1 months, the 5-year OS and 5-year PFS rates were 82.4% and 63.4%, respectively. The most common adverse events were grade 3 to 4 neutropenia (73.5%) and febrile neutropenia (21%).

Conclusions: Sequential chemoradiotherapy using DICE-L followed by radiotherapy is an effective treatment modality for stage I to IIE ENKTL and is safe with acceptable toxicity.
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http://dx.doi.org/10.21037/atm-21-3525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350702PMC
July 2021

First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety results of the randomised, phase III CHANGE-2 trial.

Eur J Cancer 2021 10 18;156:35-45. Epub 2021 Aug 18.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. Electronic address:

Background: The EXTREME regimen (chemotherapy [CT; cisplatin/carboplatin and 5-fluorouracil]) plus cetuximab is a standard-of-care first-line (1L) treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), as supported by international guidelines. The phase III CHANGE-2 trial assessed the efficacy and safety of a modified CT regimen (with a reduced dose of both components) and cetuximab versus CT for the 1L treatment of Chinese patients with R/M SCCHN.

Methods: Patients were randomised to receive up to six cycles of CT plus cetuximab followed by cetuximab maintenance until progressive disease or CT alone. The primary end-point was the progression-free survival (PFS) time assessed by the independent review committee (IRC).

Results: Overall, 243 patients were randomised (164 to CT plus cetuximab; 79 to CT). The hazard ratios for PFS by IRC and overall survival (OS) were 0.57 (95% CI: 0.40-0.80; median: 5.5 versus 4.2 months) and 0.69 (95% CI: 0.50-0.93; median: 11.1 versus 8.9 months), respectively, in favour of CT plus cetuximab. The objective response rates (ORR) by IRC were 50.0% and 26.6% with CT plus cetuximab and CT treatment, respectively. Treatment-emergent adverse events of maximum grade 3 or 4 occurred in 61.3% (CT plus cetuximab) and 48.7% (CT) of patients.

Conclusions: CHANGE-2 showed an improved median PFS, median OS and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regimen, with no new or unexpected safety findings, thereby confirming CT plus cetuximab as an effective and safe 1L treatment for Chinese patients with R/M SCCHN.

Clinical Trial Registration Number: NCT02383966.
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http://dx.doi.org/10.1016/j.ejca.2021.06.039DOI Listing
October 2021

Tree mycorrhizal type and tree diversity shape the forest soil microbiota.

Environ Microbiol 2021 Jul 30. Epub 2021 Jul 30.

Department of Community Ecology, UFZ-Helmholtz Centre for Environmental Research, Theodor-Lieser-Str. 4, Halle (Saale), D-06120, Germany.

There is limited knowledge on how the association of trees with different mycorrhizal types shapes soil microbial communities in the context of changing tree diversity levels. We used arbuscular (AM) and ectomycorrhizal (EcM) tree species as con- and heterospecific tree species pairs (TSPs), which were established in plots of three tree diversity levels including monocultures, two-species mixtures and multi-tree species mixtures in a tree diversity experiment in subtropical China. We found that the tree mycorrhizal type had a significant effect on fungal but not bacterial alpha diversity. Furthermore, only EcM but not AM TSPs fungal alpha diversity increased with tree diversity, and the differences between AM and EcM TSPs disappeared in multi-species mixtures. Tree mycorrhizal type, tree diversity and their interaction had significant effects on fungal community composition. Neither fungi nor bacteria showed any significant compositional variation in TSPs located in multi-species mixtures. Accordingly, the most influential taxa driving the tree mycorrhizal differences at low tree diversity were not significant in multi-tree species mixtures. Collectively, our results indicate that tree mycorrhizal type is an important factor determining the diversity and community composition of soil microbes, and higher tree diversity levels promote convergence of the soil microbial communities. SIGNIFICANCE STATEMENT: More than 90% of terrestrial plants have symbiotic associations with mycorrhizal fungi which could influence the coexisting microbiota. Systematic understanding of the individual and interactive effects of tree mycorrhizal type and tree species diversity on the soil microbiota is crucial for the mechanistic comprehension of the role of microbes in forest soil ecological processes. Our tree species pair (TSP) concept coupled with random sampling within and across the plots, allowed us the unbiased assessment of tree mycorrhizal type and tree diversity effects on the tree-tree interaction zone soil microbiota. Unlike in monocultures and two-species mixtures, we identified species-rich and converging fungal and bacterial communities in multi-tree species mixtures. Consequently, we recommend planting species-rich mixtures of EcM and AM trees, for afforestation and reforestation regimes. Specifically, our findings highlight the significance of tree mycorrhizal type in studying 'tree diversity - microbial diversity - ecosystem function' relationships.
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http://dx.doi.org/10.1111/1462-2920.15690DOI Listing
July 2021

[Experience in the diagnosis and treatment of the postoperative complications of craniopharyngiomas through expanded endoscopic endonasal transsphenoidal approach].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2021 Jun;35(6):505-510

Department of Otorhinolaryngology Head and Neck Surgery,Tianjin Huanhu Hospital,Tianjin,300350,China.

To summarize the clinical characteristics of the postoperative complications of surgical resection of craniopharyngiomas through expanded endoscopic endonasal transsphenoidal approach (EEETA). Strategies for prevention and management were also discussed. The clinical data of the patients who were treated through EEETA were retrospectively reviewed. The occurrence of post-operative complications were recorded. Partial removal of the tumors were accomplished in 11 cases and subtotal removal in 4 cases. The major postoperative complications were anterior pituitary hypofunction(11/15), diabetes insipidus(8/15), epistaxis(3/15), cerebrospinal fluid rhinorrhea(1/15). The cases were treated symptomatically or by re-operation. Of all the cases,10 patients were improved,1 patient had drowsiness,3 suffered from multiple organ failure,and 1 patient died. To prevent and reduce the postoperative complications of EEETA, first of all, it is essential to evaluate the need for surgical intervention and perform a comprehensive preoperative assessment. Critical nerves and vessels should be preserved carefully during operation for the sake of avoiding injuries normal pituitary and hypothalamus. Furthermore, reconstruction of the skull base is critical. The standard procedure of nasal endoscopy and the experience of the surgeons are quite significant, while the operation needs multidisciplinary collaborations.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2021.06.005DOI Listing
June 2021

Metabolic engineering strategies for sesquiterpene production in microorganism.

Crit Rev Biotechnol 2021 Jul 13:1-20. Epub 2021 Jul 13.

College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, PR China.

Sesquiterpenes are a large variety of terpene natural products, widely existing in plants, fungi, marine organisms, insects, and microbes. Value-added sesquiterpenes are extensively used in industries such as: food, drugs, fragrances, and fuels. With an increase in market demands and the price of sesquiterpenes, the biosynthesis of sesquiterpenes by microbial fermentation methods from renewable feedstocks is acquiring increasing attention. Synthetic biology provides robust tools of sesquiterpene production in microorganisms. This review presents a summary of metabolic engineering strategies on the hosts and pathway engineering for sesquiterpene production. Advances in synthetic biology provide new strategies on the creation of desired hosts for sesquiterpene production. Especially, metabolic engineering strategies for the production of sesquiterpenes such as: amorphadiene, farnesene, bisabolene, and caryophyllene are emphasized in: , , and other microorganisms. Challenges and future perspectives of the bioprocess for translating sesquiterpene production into practical industrial work are also discussed.
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http://dx.doi.org/10.1080/07388551.2021.1924112DOI Listing
July 2021

Human biomonitoring of toxic and essential metals in younger elderly, octogenarians, nonagenarians and centenarians: Analysis of the Healthy Ageing and Biomarkers Cohort Study (HABCS) in China.

Environ Int 2021 11 19;156:106717. Epub 2021 Jun 19.

China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China; School of Public Health, Anhui Medical University, Hefei, Anhui, China. Electronic address:

Background: Metals can be either toxic or essential to health, as they play different role in oxidative stress and metabolic homeostasis during the ageing process. Population-based biomonitoring have documented levels and ranges in concentrations among general population of 0-79 years of age. In people aged 80 and above, toxic metals and essential metals may have different risk profiles, and thus need to be better studied.

Objective: Our aim is to investigate concentrations of toxic metals (arsenic, cadmium, lead and mercury) and essential metals (chromium, cobalt, molybdenum, manganese, nickel and selenium) and their role in diseases, nutritional status among younger elderly, octogenarians, nonagenarians and centenarians.

Methods: A total of 932 younger elderly, 643 octogenarians, 540 nonagenarians, 386 centenarians were included from the cross-sectional Healthy Aging and Biomarkers Cohort Study in 2017-2018. Blood or urine biological substrates were collected from each participant to determine the concentrations of toxic metals and essential metals by inductively coupled plasma mass spectrometry. Random forest was constructed to rank the importance of toxic metals and essential metals in longevity. LASSO penalized regressions were performed to select the most significant metals associated with diseases and nutritional status, of which simultaneously included all metals and adjusted for the confounding factors.

Results: Compared to women, we found higher biomarker concentrations in men for toxic metals (41.2 µg/L vs 34.4 µg/L for blood lead, 1.56 µg/L vs 1.19 µg/L for blood mercury) and lower concentration of essential metals (0.48 µg/L vs 0.58 µg/L for blood molybdenum, 10.0 µg/L vs 11.1 µg/L for blood manganese). These factors may contribute to gender difference observed in longevity, that women live longer than men. Blood lead and urine cadmium tended to increase with age (P <0.001); blood cobalt, molybdenum, manganese increased with age, blood selenium decreased with age while the prevalence of selenium deficiency was extremely low in centenarians. Among toxic metals and essential metals, LASSO penalized regression identified the most significant metals associated with chronic kidney disease was cadmium and arsenic; and it was manganese, cobalt, and selenium for diabetes; it was selenium, molybdenum, lead for anemia; it was mercury for underweight. In random forest model, the top four important metals in longevity were selenium, arsenic, lead and manganese both in men and women.

Conclusions: Generally, toxic metals levels were significantly higher while essential metals were relatively sufficient in Chinese centenarians. Toxic metals and essential metals played different role in diseases, nutritional status and longevity in the process of aging. Our research provided real world evidence of biomonitoring reference values to be used for the ongoing population health surveillance in longevity.
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http://dx.doi.org/10.1016/j.envint.2021.106717DOI Listing
November 2021

Reduced microbial stability in the active layer is associated with carbon loss under alpine permafrost degradation.

Proc Natl Acad Sci U S A 2021 06;118(25)

University of Chinese Academy of Sciences, 100049 Beijing, China.

Permafrost degradation may induce soil carbon (C) loss, critical for global C cycling, and be mediated by microbes. Despite larger C stored within the active layer of permafrost regions, which are more affected by warming, and the critical roles of Qinghai-Tibet Plateau in C cycling, most previous studies focused on the permafrost layer and in high-latitude areas. We demonstrate in situ that permafrost degradation alters the diversity and potentially decreases the stability of active layer microbial communities. These changes are associated with soil C loss and potentially a positive C feedback. This study provides insights into microbial-mediated mechanisms responsible for C loss within the active layer in degraded permafrost, aiding in the modeling of C emission under future scenarios.
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http://dx.doi.org/10.1073/pnas.2025321118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237688PMC
June 2021

Proton Detected Solid-State NMR of Membrane Proteins at 28 Tesla (1.2 GHz) and 100 kHz Magic-Angle Spinning.

Biomolecules 2021 05 18;11(5). Epub 2021 May 18.

Department for NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany.

The available magnetic field strength for high resolution NMR in persistent superconducting magnets has recently improved from 23.5 to 28 Tesla, increasing the proton resonance frequency from 1 to 1.2 GHz. For magic-angle spinning (MAS) NMR, this is expected to improve resolution, provided the sample preparation results in homogeneous broadening. We compare two-dimensional (2D) proton detected MAS NMR spectra of four membrane proteins at 950 and 1200 MHz. We find a consistent improvement in resolution that scales superlinearly with the increase in magnetic field for three of the four examples. In 3D and 4D spectra, which are now routinely acquired, this improvement indicates the ability to resolve at least 2 and 2.5 times as many signals, respectively.
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http://dx.doi.org/10.3390/biom11050752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157399PMC
May 2021

(Pro)renin receptor antagonist PRO20 attenuates nephrectomy-induced nephropathy in rats via inhibition of intrarenal RAS and Wnt/β-catenin signaling.

Physiol Rep 2021 06;9(11):e14881

Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, China.

Introduction: (Pro)renin receptor has emerged as a new member of the renin-angiotensin system implicated in the pathogenesis of chronic kidney disease (CKD). Herein we report characterization of the therapeutic potential of (pro)renin receptor (PRR) antagonist PRO20 in 5/6 nephrectomy (5/6Nx) rats.

Methods: Male Wistar rats underwent 5/6Nx followed by treatment with vehicle or received daily injections of a PRR inhibitor PRO20 (700 μg/kg) via the 3 s.c. Sham group served as a control.

Results: As compared with the sham control, the 5/6Nx rats exhibited significant increases in proteinuria, glomerulosclerosis, tubular injury, and interstitial inflammation in the remnant kidneys. Treatment with PRO20 significantly attenuated these abnormalities, as evidenced by reduced expression of fibronectin, α-SMA, collagen 1, TGF-β1, IL-6, IL-8, IL-1β, MCP-1 and increased expression of E-cadherin. Increased urinary/renal levels of renin activity, angiotensinogen (AGT), and Angiotensin II (Ang II) by 5/6Nx, which were all ameliorated by PRO20. Renal PRR, the secreted proteolytic fragment of PRR (sPRR) in renal and urinary, were all elevated in 5/6Nx rats. Moreover, our results revealed that renal Wnt3A and β-catenin expression were upregulated during 5/6Nx, which were all attenuated by PRO20.

Conclusions: Overall we conclude that in vivo antagonism of PRR with PRO20 will improve 5/6Nx-induced CKD mainly through inhibition of intrarenal RAS and Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.14814/phy2.14881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165733PMC
June 2021

Development and Validation of a Novel Prognostic Model for Acute Myeloid Leukemia Based on Immune-Related Genes.

Front Immunol 2021 5;12:639634. Epub 2021 May 5.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The prognosis of acute myeloid leukemia (AML) is closely related to immune response changes. Further exploration of the pathobiology of AML focusing on immune-related genes would contribute to the development of more advanced evaluation and treatment strategies. In this study, we established a novel immune-17 signature based on transcriptome data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We found that immune biology processes and transcriptional dysregulations are critical factors in the development of AML through enrichment analyses. We also formulated a prognostic model to predict the overall survival of AML patients by using LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Furthermore, we incorporated the immune-17 signature to improve the prognostic accuracy of the ELN2017 risk stratification system. We concluded that the immune-17 signature represents a novel useful model for evaluating AML survival outcomes and may be implemented to optimize treatment selection in the next future.
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http://dx.doi.org/10.3389/fimmu.2021.639634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131848PMC
September 2021

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism.

Front Oncol 2021 6;11:663360. Epub 2021 Apr 6.

Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in a low concentration, while inducing the apoptosis of B-ALL cells in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.
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http://dx.doi.org/10.3389/fonc.2021.663360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056175PMC
April 2021

Linkage between microbial shift and ecosystem functionality.

Authors:
Yanfen Wang Kai Xue

Glob Chang Biol 2021 07 3;27(14):3197-3199. Epub 2021 May 3.

College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, China.

Exploring the linkage between microbial shifts and ecological processes or ecosystem functionality is a central focus in microbial ecology, but faces considerable obstacles, including the gap between DNA-based information and biochemical processes, as well as the asynchronization in microbial taxonomic shifts and their functionality change. Despite these issues, the well-established linkage between functional genes (reflecting genetic potential) and carbon release via laboratory incubation (reflecting field potential) is a good preliminary step that provides clues about the magnitude of in situ permafrost carbon release under permafrost thaw on the basis of microbial functional gene changes.
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http://dx.doi.org/10.1111/gcb.15615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251610PMC
July 2021
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