Publications by authors named "Liang Tong"

294 Publications

Quantitative trait locus mapping analysis of multiple traits when using genotype data with potential errors.

PeerJ 2021 24;9:e12187. Epub 2021 Sep 24.

School of Science, Harbin University of Science and Technology, Harbin, P. R. China.

Background: Quantitative trait locus (QTL) analysis aims to locate and estimate the effects of the genes influencing quantitative traits and infer the relationship between gene variants and changes in phenotypic characteristics using statistical methods. Some methods have been developed to map QTLs of multiple traits in the case of no genotype error in a given dataset. However, practical genetic data that people use may contain some potential errors because of the limitations of biotechnology. Common genetic data correction methods can only reduce errors, but cannot calculate the degree of error. In this paper, we propose a QTL mapping strategy for multiple traits in the presence of genotype errors.

Methods: The additive effect, dominant effect, recombination rate, error rate, and other parameters of QTLs can be simultaneously obtained using this new method in the framework of multiple-interval mapping.

Results: Our simulation results show that the accuracy of parameter estimation can be improved by considering the errors of marker genotypes during the analysis of genetic data. Real data analysis also shows that the new method proposed in this paper can map the QTLs of multiple traits more accurately.
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http://dx.doi.org/10.7717/peerj.12187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475548PMC
September 2021

Study on the identification of resistance of rice blast based on near infrared spectroscopy.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Sep 27;266:120439. Epub 2021 Sep 27.

Communication and Electronic Engineering Institute, Qiqihar University, China.

Rice Blast is the most devastating rice disease which poses a serious threat to the safe production of rice. The most effective way to prevent rice blast is to cultivate the rice varieties that have resistance to the disease, however, traditional resistance testing requires professional personnel, a tedious process, long determination time and high cost. In order to quickly identify different resistant rice seeds which are difficult to distinguish with the naked eye, a rapid non-destructive identification method based on Near-Infrared Spectroscopy (NIRS) was proposed. Four different types of resistant rice seeds (high resistance, high susceptibility, susceptibility and resistance) came from in HeiLongjiang province of China were selected as the research objects. A total of 240 spectral data (60 from each variety) were scanned by the NIR spectrometer. The BP neural network (BP), Support Vector Machines (SVM), Probabilistic Neural Network (PNN) models were established based on the original spectral data in the full-spectrum (11520-4000 cm). Among all, Raw-BP has the best identification accuracy which reaches 100% with an iteration time of 869 s. After extracting the feature wavelengths by successive projections algorithm (SPA) on the spectral data, Raw-SPA-BP, Raw-SPA-SVM and Raw-SPA-PNN models were established. The accuracy of these three models didn't improve. But the iteration time of the SPA-BP model was shortened to 791 s. Another group of BP, SVM, and PNN models were established after using different spectral pretreatment methods and the SPA feature extraction. After Multivariate Scatter Correction (MSC), the accuracy of the MSC-SPA-BP model was still 100% and the iteration time was shortened to 840 s, which is 1/30 of the time at which the original data model was formed. The accuracy of the MSC-SPA-PNN model increased from 60% to 90% and the accuracy of the MSC-SPA-SVM model increased from 60% to 85%. Based on the comparison analysis of the models mentioned above, a best neural network identification model of the MSC-SPA-BP with 513 inputs, 8 hidden layers and 4 outputs was established. Its classification accuracy reached 100% with an iteration time of 29 s, indicating that the MSC-SPA-BP model can completely achieve identification of four different resistant rice seeds. Therefore, the proposed method of the BP neural network identification model based on NIRS can be fully applied to the non-destructive rapid identification of rice seeds. Meanwhile, it provides a reference for the rapid identification of other crop seeds.
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http://dx.doi.org/10.1016/j.saa.2021.120439DOI Listing
September 2021

Visualization of individual cell division history in complex tissues using iCOUNT.

Cell Stem Cell 2021 Sep 8. Epub 2021 Sep 8.

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

The division potential of individual stem cells and the molecular consequences of successive rounds of proliferation remain largely unknown. Here, we developed an inducible cell division counter (iCOUNT) that reports cell division events in human and mouse tissues in vitro and in vivo. Analyzing cell division histories of neural stem/progenitor cells (NSPCs) in the developing and adult brain, we show that iCOUNT can provide novel insights into stem cell behavior. Further, we use single-cell RNA sequencing (scRNA-seq) of iCOUNT-labeled NSPCs and their progenies from the developing mouse cortex and forebrain-regionalized human organoids to identify functionally relevant molecular pathways that are commonly regulated between mouse and human cells, depending on individual cell division histories. Thus, we developed a tool to characterize the molecular consequences of repeated cell divisions of stem cells that allows an analysis of the cellular principles underlying tissue formation, homeostasis, and repair.
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http://dx.doi.org/10.1016/j.stem.2021.08.012DOI Listing
September 2021

U7 deciphered: the mechanism that forms the unusual 3' end of metazoan replication-dependent histone mRNAs.

Biochem Soc Trans 2021 Aug 5. Epub 2021 Aug 5.

Department of Biological Sciences, Columbia University, New York, NY 10027, U.S.A.

In animal cells, replication-dependent histone mRNAs end with a highly conserved stem-loop structure followed by a 4- to 5-nucleotide single-stranded tail. This unique 3' end distinguishes replication-dependent histone mRNAs from all other eukaryotic mRNAs, which end with a poly(A) tail produced by the canonical 3'-end processing mechanism of cleavage and polyadenylation. The pioneering studies of Max Birnstiel's group demonstrated nearly 40 years ago that the unique 3' end of animal replication-dependent histone mRNAs is generated by a distinct processing mechanism, whereby histone mRNA precursors are cleaved downstream of the stem-loop, but this cleavage is not followed by polyadenylation. The key role is played by the U7 snRNP, a complex of a ∼60 nucleotide U7 snRNA and many proteins. Some of these proteins, including the enzymatic component CPSF73, are shared with the canonical cleavage and polyadenylation machinery, justifying the view that the two metazoan pre-mRNA 3'-end processing mechanisms have a common evolutionary origin. The studies on U7 snRNP culminated in the recent breakthrough of reconstituting an entirely recombinant human machinery that is capable of accurately cleaving histone pre-mRNAs, and determining its structure in complex with a pre-mRNA substrate (with 13 proteins and two RNAs) that is poised for the cleavage reaction. The structure uncovered an unanticipated network of interactions within the U7 snRNP and a remarkable mechanism of activating catalytically dormant CPSF73 for the cleavage. This work provides a conceptual framework for understanding other eukaryotic 3'-end processing machineries.
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http://dx.doi.org/10.1042/BST20210323DOI Listing
August 2021

A Rationally Designed c-di-AMP Förster Resonance Energy Transfer Biosensor To Monitor Nucleotide Dynamics.

J Bacteriol 2021 Sep 8;203(19):e0008021. Epub 2021 Sep 8.

Department of Microbiology, University of Washington, Seattle, Washington, USA.

3'3'-Cyclic di-AMP (c-di-AMP) is an important nucleotide second messenger found throughout the bacterial domain of life. c-di-AMP is essential in many bacteria and regulates a diverse array of effector proteins controlling pathogenesis, cell wall homeostasis, osmoregulation, and central metabolism. Despite the ubiquity and importance of c-di-AMP, methods to detect this signaling molecule are limited, particularly at single-cell resolution. In this work, crystallization of the Listeria monocytogenes c-di-AMP effector protein Lmo0553 enabled structure-guided design of a Förster resonance energy transfer (FRET)-based biosensor, which we have named CDA5. CDA5 is a fully genetically encodable, specific, and reversible biosensor which allows the detection of c-di-AMP dynamics both and within live cells in a nondestructive manner. Our initial studies identified a distribution of c-di-AMP in Bacillus subtilis populations first grown in Luria broth and then resuspended in diluted Luria broth compatible with fluorescence analysis. Furthermore, we found that B. subtilis mutants lacking either a c-di-AMP phosphodiesterase and cyclase have higher and lower FRET responses, respectively. These findings provide novel insight into the c-di-AMP distribution within bacterial populations and establish CDA5 as a powerful platform for characterizing new aspects of c-di-AMP regulation. c-di-AMP is an important nucleotide second messenger for which detection methods are severely limited. In this work we engineered and implemented a c-di-AMP-specific FRET biosensor to remedy this dearth. We present this biosensor, CDA5, as a versatile tool to investigate previously intractable facets of c-di-AMP biology.
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http://dx.doi.org/10.1128/JB.00080-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425405PMC
September 2021

A real-time fluorescence assay for CPSF73, the nuclease for pre-mRNA 3'-end processing.

RNA 2021 10 6;27(10):1148-1154. Epub 2021 Jul 6.

Department of Biological Sciences, Columbia University, New York, New York 10027, USA.

CPSF73 is the endonuclease that catalyzes the cleavage reaction for 3'-end processing of mRNA precursors (pre-mRNAs) in two distinct machineries, a canonical machinery for the majority of pre-mRNAs and a U7 snRNP (U7 machinery) for replication-dependent histone pre-mRNAs in animal cells. CPSF73 also possesses 5'-3' exonuclease activity in the U7 machinery, degrading the downstream cleavage product after the endonucleolytic cleavage. Recent studies show that CPSF73 is a potential target for developing anticancer, antimalarial, and antiprotozoal drugs, spurring interest in identifying new small-molecule inhibitors against this enzyme. CPSF73 nuclease activity has so far been demonstrated using a gel-based end-point assay, using radiolabeled or fluorescently labeled RNA substrates. By taking advantage of unique properties of the U7 machinery, we have developed a novel, real-time fluorescence assay for the nuclease activity of CPSF73. This assay is facile and high-throughput, and should also be helpful for the discovery of new CPSF73 inhibitors.
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http://dx.doi.org/10.1261/rna.078764.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457007PMC
October 2021

Reconstitution and biochemical assays of an active human histone pre-mRNA 3'-end processing machinery.

Methods Enzymol 2021 3;655:291-324. Epub 2021 May 3.

Department of Biological Sciences, Columbia University, New York, NY, United States. Electronic address:

In animal cells, replication-dependent histone pre-mRNAs are processed at the 3'-end by an endonucleolytic cleavage carried out by the U7 snRNP, a machinery that contains the U7 snRNA and many protein subunits. Studies on the composition of this machinery and understanding of its role in 3'-end processing were greatly facilitated by the development of an in vitro system utilizing nuclear extracts from mammalian cells 35 years ago and later from Drosophila cells. Most recently, recombinant expression and purification of the components of the machinery have enabled the full reconstitution of an active machinery and its complex with a model pre-mRNA substrate, using 13 proteins and 2 RNAs, and the determination of the structure of this active machinery. This chapter presents protocols for preparing nuclear extracts containing endogenous processing machinery, for assembling semi-recombinant and fully reconstituted machineries, and for histone pre-mRNA 3'-end processing assays with these samples.
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http://dx.doi.org/10.1016/bs.mie.2021.03.021DOI Listing
July 2021

Segmentation of acetowhite region in uterine cervical image based on deep learning.

Technol Health Care 2021 Jun 25. Epub 2021 Jun 25.

Department of Information Engineering, Nanchang Hangkong University, Nanchang, Jiangxi 330036, China.

Background: Acetowhite (AW) region is a critical physiological phenomenon of precancerous lesions of cervical cancer. An accurate segmentation of the AW region can provide a useful diagnostic tool for gynecologic oncologists in screening cervical cancers. Traditional approaches for the segmentation of AW regions relied heavily on manual or semi-automatic methods.

Objective: To automatically segment the AW regions from colposcope images.

Methods: First, the cervical region was extracted from the original colposcope images by k-means clustering algorithm. Second, a deep learning-based image semantic segmentation model named DeepLab V3+ was used to segment the AW region from the cervical image.

Results: The results showed that, compared to the fuzzy clustering segmentation algorithm and the level set segmentation algorithm, the new method proposed in this study achieved a mean Jaccard Index (JI) accuracy of 63.6% (improved by 27.9% and 27.5% respectively), a mean specificity of 94.9% (improved by 55.8% and 32.3% respectively) and a mean accuracy of 91.2% (improved by 38.6% and 26.4% respectively). A mean sensitivity of 78.2% was achieved by the proposed method, which was 17.4% and 10.1% lower respectively. Compared to the image semantic segmentation models U-Net and PSPNet, the proposed method yielded a higher mean JI accuracy, mean sensitivity and mean accuracy.

Conclusion: The improved segmentation performance suggested that the proposed method may serve as a useful complimentary tool in screening cervical cancer.
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http://dx.doi.org/10.3233/THC-212890DOI Listing
June 2021

Identification of zinc pollution in rice plants based on two characteristic variables.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Nov 4;261:120043. Epub 2021 Jun 4.

Communication and Electronic Engineering Institute, Qiqihar University, Qiqihar 161006, People's Republic of China.

Traditional chemical methods used to measure the zinc content in rice plants are time-consuming, laborious, requires reagents, and have a limited monitoring range, while the Raman spectroscopy method has the advantage of being fast, non-destructive, and requires no reagents. Unfortunately, the identification accuracy of the Raman partial least squares (PLS) model based on principal components is only 53.33%. To boost this, a One-Way ANOVA method was used to extract the characteristic variables in the Raman spectra. Based on these Raman variables, a model for identifying zinc stressed samples was established. The identification accuracy was improved to 70% but still fell short of the measurement requirements. To further enhance these results, the Raman spectrum was decomposed into components based on the Hilbert Vibration Decomposition (HVD) method. Using characteristic variables of the Raman spectrum and its HVD components to establish a PLS model, the identification accuracy of the test set is raised to 90.25%. These results are a significant improvement from those obtained using a model solely based on the Raman spectral characteristic variables, revealing that HVD components provide highly effective identification information. A Raman modeling method based on the characteristic variables of the HVD component is an innovative way for improving the accuracy of Raman detection, especially for the measurement of trace substances.
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http://dx.doi.org/10.1016/j.saa.2021.120043DOI Listing
November 2021

Therapeutic effects and prognostic factors of I brachytherapy for pelvic recurrence after early cervical cancer surgery.

Sci Rep 2021 05 31;11(1):11356. Epub 2021 May 31.

Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, Guangdong, China.

To investigate the efficacy of I seed implantation in the treatment regimen of pelvic recurrence after early cervical cancer surgery and to analyse prognostic factors. To evaluate efficacy and analyse prognostic factors of I seed implantation for pelvic recurrence after early cervical cancer surgery. A prospective study was conducted on 62 patients who experienced pelvic recurrence after early cervical cancer surgery between August 2005 and September 2015. The 62 patients were treated and assessed in 2 groups (n = 30). All 62 patients were randomized into two groups that received two different treatment regimens: the treatment group (n = 30), which received I particle implantation therapy, and the control group (n = 32), which received whole-pelvic irradiation using the anteroposterior/posteroanterior field and cisplatin-based concurrent chemoradiation therapy. The efficacy/efficiency of I seed implantation and prognostic factors were analysed by logistic regression. Overall survival was determined by Kaplan-Meier analysis. Multivariate analysis results were obtained by the Cox proportional hazards regression model. The effective control rates at 1, 3, 6 and 12 months were 76.7%, 80.0%, 83.3%, and 86.7% in the I particle implantation group. The total effective control rates at 1, 3, 6 and 12 months were 65.6%, 65.5%, 62.5%, and 71.9% in the chemoradiotherapy group. Significant differences were observed between the two groups. The overall survival rates at 1, 2, 3, 4, and 5 years and the median overall were 96.7%, 93.3%, 86.7%, 71.9%, 65.6% and 4.34 years, respectively, in the I seed implantation group and 81.3%, 71.9%, 62.5%, 56.3%, 53.1% and 3.59 years, respectively, in the control group. There were statistically significant differences in survival rates depending on the diameter of the largest recurrent pelvic tumour (χ = 6.611, P = 0.010). The multivariate analysis showed that the survival rates were related to the diameter of the largest recurrent pelvic tumour (χ = 4.538, P = 0.033). I implantation is an effective, safe, and promising method for the treatment of pelvic recurrence after early cervical cancer surgery. The diameter of the recurrent pelvic tumour was identified as a significant independent prognostic factor in patients who received I implantation.
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http://dx.doi.org/10.1038/s41598-021-90007-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166881PMC
May 2021

The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin.

Cell Rep 2021 May;35(7):109137

Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address:

Oncogenic histone lysine-to-methionine mutations block the methylation of their corresponding lysine residues on wild-type histones. One attractive model is that these mutations sequester histone methyltransferases, but genome-wide studies show that mutant histones and histone methyltransferases often do not colocalize. Using chromatin immunoprecipitation sequencing (ChIP-seq), here, we show that, in fission yeast, even though H3K9M-containing nucleosomes are broadly distributed across the genome, the histone H3K9 methyltransferase Clr4 is mainly sequestered at pericentric repeats. This selective sequestration of Clr4 depends not only on H3K9M but also on H3K14 ubiquitylation (H3K14ub), a modification deposited by a Clr4-associated E3 ubiquitin ligase complex. In vitro, H3K14ub synergizes with H3K9M to interact with Clr4 and potentiates the inhibitory effects of H3K9M on Clr4 enzymatic activity. Moreover, binding kinetics show that H3K14ub overcomes the Clr4 aversion to H3K9M and reduces its dissociation. The selective sequestration model reconciles previous discrepancies and demonstrates the importance of protein-interaction kinetics in regulating biological processes.
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http://dx.doi.org/10.1016/j.celrep.2021.109137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167812PMC
May 2021

Structural basis for a bacterial Pip system plant effector recognition protein.

Proc Natl Acad Sci U S A 2021 03;118(10)

Department of Biological Sciences, Columbia University, New York, NY 10027;

A number of plant-associated proteobacteria have LuxR family transcription factors that we refer to as PipR subfamily members. PipR proteins play roles in interactions between bacteria and their plant hosts, and some are important for bacterial virulence of plants. We identified an ethanolamine derivative, -(2-hydroxyethyl)-2-(2-hydroxyethylamino) acetamide (HEHEAA), as a potent effector of PipR-mediated gene regulation in the plant endophyte GM79. HEHEAA-dependent PipR activity requires an ATP-binding cassette-type active transport system, and the periplasmic substrate-binding protein (SBP) of that system binds HEHEAA. To begin to understand the molecular basis of PipR system responses to plant factors we crystallized a HEHEAA-responsive SBP in the free- and HEHEAA-bound forms. The SBP, which is similar to peptide-binding SBPs, was in a closed conformation. A narrow cavity at the interface of its two lobes is wide enough to bind HEHEAA, but it cannot accommodate peptides with side chains. The polar atoms of HEHEAA are recognized by hydrogen-bonding interactions, and additional SBP residues contribute to the binding site. This binding mode was confirmed by a structure-based mutational analysis. We also show that a closely related SBP from the plant pathogen pv DC3000 does not recognize HEHEAA. However, a single amino acid substitution in the presumed effector-binding pocket of the SBP converted it to a weak HEHEAA-binding protein. The PipR depends on a plant effector for activity, and our findings imply that different PipR-associated SBPs bind different effectors.
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http://dx.doi.org/10.1073/pnas.2019462118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958261PMC
March 2021

Fluorescence Switchable Conjugated Polymer Microdisk Arrays by Cosolvent Vapor Annealing.

Polymers (Basel) 2021 Jan 15;13(2). Epub 2021 Jan 15.

Department of Materials Science, Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8573, Ibaraki, Japan.

Depositing minute light emitters into a regular array is a basic but essential technique in display technology. However, conventional lithographic methodologies involve multistep and energy-consuming processes. Here, we develop a facile method in which organic and polymeric fluorescent dyes spontaneously aggregate to form a patterned microarray. We find that a thin film of fluorescent π-conjugated polymer transforms into micrometer-sized aggregates when exposed to binary organic vapor at ambient temperature. The arrayed microaggregates can be formed over the whole substrate surface when using a quartz substrate that is prepatterned with regular hydrophilic boxes and hydrophobic grids. The resultant microarray is applicable to optical memories and displays when photoswitchable fluorophores are doped into the polymer matrix.
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http://dx.doi.org/10.3390/polym13020269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829903PMC
January 2021

Diagnosis of cervical precancerous lesions based on multimodal feature changes.

Comput Biol Med 2021 03 5;130:104209. Epub 2021 Jan 5.

College of Information Engineering, Nanchang Hangkong University, Nanchang, China. Electronic address:

To realize the automatic diagnosis of cervical intraepithelial neoplasia (CIN) cases by preacetic acid test and postacetic acid test colposcopy images, this paper proposes a method of cervical precancerous lesion diagnosis based on multimodal feature changes. First, the preacetic acid test and postacetic acid test colposcopy images were registered based on cross-correlation and projection transformation, and then the cervical region was extracted by the k-means clustering algorithm. Finally, a deep learning network was used to extract features and classify the preacetic acid test and postacetic acid test cervical images after registration. Finally, the proposed method achieves a classification accuracy of 86.3%, a sensitivity of 84.1%, and a specificity of 89.8% in 60 test cases. Experimental results show that this method can make better use of the multimodal features of colposcopy images and has lower requirements for medical staff in the process of data acquisition. It has certain clinical significance in cervical cancer precancerous lesion screening systems.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104209DOI Listing
March 2021

Crystal structure of a thermophilic fungal cyanase and its implications on the catalytic mechanism for bioremediation.

Sci Rep 2021 01 11;11(1):277. Epub 2021 Jan 11.

Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban, 4000, South Africa.

Cyanase catalyzes the bicarbonate-dependent degradation of cyanate to produce ammonia and carbon dioxide, and ammonia is a considerable alternative nitrogen source. Strikingly, the cyanase from the thermophilic fungus Thermomyces lanuginosus (Tl-Cyn) has the highest catalytic efficiency reported among these enzymes. However, its molecular mechanism of action is not clearly understood, because currently there is no structural information available on fungal cyanases. Here we report the crystal structure of Tl-Cyn in complex with inhibitors malonate and formate at 2.2 Å resolution. The structure reveals extensive interactions at the subunit interfaces in a dimer, and a decamer is formed by a pentamer of these dimers. Our biochemical, kinetic and mutagenesis studies confirm the structural observations on the complex and provide further insights into its catalytic mechanism and inhibition. The structure has also aided the creation of a mutant enzyme with enhanced catalytic activity, and such enzymes may have the potential for biotechnological applications, including biotransformation and bioremediation. Moreover, other fungal cyanases with potentially high catalytic activity could also be predicted based on the Tl-Cyn structure, as the active site region among fungal cyanases are highly conserved.
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http://dx.doi.org/10.1038/s41598-020-79489-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801690PMC
January 2021

A multiaxial molecular ferroelectric with record high designed by intermolecular interaction modulation.

Chem Commun (Camb) 2021 Jan;57(7):943-946

School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, People's Republic of China.

Through precise and ingenious molecular modification, we successfully obtained a multiaxial ferroelectric, [FEtDabco]ZnI3 (N-fluoroethyl-N'-ZnI3-1,4-diazabicyclo[2.2.2]octonium), with a record high Tc (540 K) among molecular ferroelectrics, which is promising for application under extreme thermal conditions.
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http://dx.doi.org/10.1039/d0cc07377fDOI Listing
January 2021

How to diSARM the executioner of axon degeneration.

Authors:
Liang Tong

Nat Struct Mol Biol 2021 01;28(1):10-12

Department of Biological Sciences, Columbia University, New York, NY, USA.

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http://dx.doi.org/10.1038/s41594-020-00545-7DOI Listing
January 2021

circ_100984-miR-432-3p axis regulated c-Jun/YBX-1/β-catenin feedback loop promotes bladder cancer progression.

Cancer Sci 2021 Apr 10;112(4):1429-1442. Epub 2021 Feb 10.

Department of Urology, Xiangya Hospital, Central South University, Changsha, China.

Bladder cancer (BC) is one of the most commonly diagnosed cancers globally. Recently, circular RNAs (circRNAs) have been revealed to participate in BC progression with diverse mechanisms. However, mechanisms of circ_100984 in BC have not been determined. Here, we found that circ_100984 and YBX-1 were high presented, while miR-432-3p was low presented in BC. Silencing of circ_100984 and YBX-1 repressed BC tumor growth, migration, and invasion in vitro and in vivo. Mechanistically, we revealed that circ_100984 served as a competing endogenous RNA that sponged miR-432-3p to indirectly regulate YBX-1 and epithelial-mesenchymal transition (EMT)-related molecules. Moreover, we confirmed that YBX-1 or c-Jun acted as a transcription regulatory factor for β-catenin or YBX-1, respectively, in BC cells. Knockdown of YBX-1 inhibited the expression of β-catenin and c-Jun, whereas downregulated c-Jun inversely repressed the expression of YBX-1 and β-catenin. Our results suggested that circ_100984-miR-432-3p axis regulated c-Jun/YBX-1/β-catenin feedback loop promotes BC progression, providing a potential therapeutic axis for BC progression.
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http://dx.doi.org/10.1111/cas.14774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019231PMC
April 2021

Hole transport free flexible perovskite solar cells with cost-effective carbon electrodes.

Nanotechnology 2021 Mar;32(10):105205

Electronic Materials Research Laboratory, Key Laboratory of the Ministry of Education & International Center for Dielectric Research, Shaanxi Engineering Research Center of Advanced Energy Materials and Devices, School of Electronic Science and Engineering, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, People's Republic of China.

Low temperature derived carbon electrodes are employed to fabricate low cost hole transport layer free perovskite solar cells, in which perovskite films annealed in glovebox and ambient air are used as the absorbers, respectively. Results suggest that the air annealed sample has bigger crystal grains and higher crystallinity, and the existence of a small amount of lead iodide which passivates grain boundaries contributes to a lower trap density. As a result, a maximum power conversion efficiency (PCE) of 13.07% was obtained on the air annealed device, which is higher than those of devices annealed in glovebox (11.25%). Furthermore, the stability of unencapsulated devices stored in wet (with humidity around 90% ± 5%) air atmosphere are investigated and the results prove that our devices exhibit good stability. In addition to rigid devices, flexible perovskite solar cells are also fabricated using the same procedure. The highest PCE of 11.53% is demonstrated on the champion flexible device, and 69% of its initial PCE can be maintained even after 2000 bending cycles with a bending radius of 2 mm. Our work provides a promising and simple rout for low-cost, air-stable, high-efficiency carbon perovskite solar cells for both large area production and flexible electronic devices industry.
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http://dx.doi.org/10.1088/1361-6528/abcf70DOI Listing
March 2021

Structure and Function of the Separase-Securin Complex.

Subcell Biochem 2021 ;96:217-232

Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.

Separase is a large cysteine protease in eukaryotes and has crucial roles in many cellular processes, especially chromosome segregation during mitosis and meiosis, apoptosis, DNA damage repair, centrosome disengagement and duplication, spindle stabilization and elongation. It dissolves the cohesion between sister chromatids by cleaving one of the subunits of the cohesin ring for chromosome segregation. The activity of separase is tightly controlled at many levels, through direct binding of inhibitory proteins as well as posttranslational modification. Dysregulation of separase activity is linked to cancer and genome instability, making it a target for drug discovery. One of the best-known inhibitors of separase is securin, which has been identified in yeast, plants, and animals. Securin forms a tight complex with separase and potently inhibits its catalytic activity. Recent structures of the separase-securin complex have revealed the molecular mechanism for the inhibitory activity of securin. A segment of securin is bound in the active site of separase, thereby blocking substrate binding. Securin itself is not cleaved by separase as its binding mode is not compatible with catalysis. Securin also has extensive interactions with separase outside the active site, consistent with its function as a chaperone to stabilize this enzyme.
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http://dx.doi.org/10.1007/978-3-030-58971-4_4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891875PMC
February 2021

Molecular mechanism for the interaction between human CPSF30 and hFip1.

Genes Dev 2020 12 29;34(23-24):1753-1761. Epub 2020 Oct 29.

Department of Biological Sciences, Columbia University, New York, New York 10027, USA.

Most eukaryotic pre-mRNAs must undergo 3'-end cleavage and polyadenylation prior to their export from the nucleus. A large number of proteins in several complexes participate in this 3'-end processing, including cleavage and polyadenylation specificity factor (CPSF) in mammals. The CPSF30 subunit contains five CCCH zinc fingers (ZFs), with ZF2-ZF3 being required for the recognition of the AAUAAA poly(A) signal. ZF4-ZF5 recruits the hFip1 subunit of CPSF, although the details of this interaction have not been characterized. Here we report the crystal structure of human CPSF30 ZF4-ZF5 in complex with residues 161-200 of hFip1 at 1.9 Å resolution, illuminating the molecular basis for their interaction. Unexpectedly, the structure reveals one hFip1 molecule binding to each ZF4 and ZF5, with a conserved mode of interaction. Our mutagenesis studies confirm that the CPSF30-hFip1 complex has 1:2 stoichiometry in vitro. Mutation of each binding site in CPSF30 still allows one copy of hFip1 to bind, while mutation of both sites abrogates binding. Our fluorescence polarization binding assays show that ZF4 has higher affinity for hFip1, with a of 1.8 nM. We also demonstrate that two copies of the catalytic module of poly(A) polymerase (PAP) are recruited by the CPSF30-hFip1 complex in vitro, and both hFip1 binding sites in CPSF30 can support polyadenylation.
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http://dx.doi.org/10.1101/gad.343814.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706699PMC
December 2020

Transcriptomic Analysis Reveals Important Roles of Lignin and Flavonoid Biosynthetic Pathways in Rice Thermotolerance During Reproductive Stage.

Front Genet 2020 15;11:562937. Epub 2020 Sep 15.

Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Agricultural College, Yangtze University, Jingzhou, China.

Rice is one of the major staple cereals in the world, but heat stress is increasingly threatening its yield. Analyzing the thermotolerance mechanism from new thermotolerant germplasms is very important for rice improvement. Here, physiological and transcriptome analyses were used to characterize the difference between two germplasms, heat-sensitive MH101 and heat-tolerant SDWG005. Two genotypes exhibited diverse heat responses in pollen viability, pollination characteristics, and antioxidant enzymatic activity in leaves and spikelets. Through cluster analysis, the global transcriptomic changes indicated that the ability of SDWG005 to maintain a steady-state balance of metabolic processes played an important role in thermotolerance. After analyses of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, we found that the thermotolerance mechanism in SDWG00 was associated with reprogramming the cellular activities, such as response to abiotic stress and metabolic reorganization. In contrast, the down-regulated genes in MH101 that appeared to be involved in DNA replication and DNA repair proofreading, could cause serious injury to reproductive development when exposed to high temperature during meiosis. Furthermore, we identified 77 and 11 differentially expressed genes (DEGs) involved in lignin and flavonoids biosynthetic pathways, respectively. Moreover, we found that more lignin deposition and flavonoids accumulation happened in SDWG005 than in MH101 under heat stress. The results indicated that lignin and flavonoid biosynthetic pathways might play important roles in rice heat resistance during meiosis.
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http://dx.doi.org/10.3389/fgene.2020.562937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522568PMC
September 2020

Causes of Variations in Sediment Yield in the Jinghe River Basin, China.

Sci Rep 2020 10 22;10(1):18054. Epub 2020 Oct 22.

Yellow River Engineering Consulting Co., Ltd, Zhengzhou, 450003, China.

The Jinghe River remains the major sediment source of the Yellow River in China; however, sediment discharge in the Jinghe River has reduced significantly since the 1950s. The objective of this study is to identify the causes of sediment yield variations in the Jinghe River Basin based on soil and water conservation methods and rainfall analyses. The results revealed that soil and water conservation projects were responsible for half of the total sediment reduction; sediment retention due to reservoirs and water diversion projects was responsible for 1.3% of the total reduction. Moreover, the Jinghe River Basin has negligible opportunity to improve its vegetation cover (currently 55% of the basin is covered with lawns and trees), and silt-arrester dams play a smaller role in reducing sediment significantly before they are entirely full. Therefore, new large-scale sediment trapping projects must be implemented across the Jinghe River Basin, where heavy rainfall events are likely to substantially increase in the future, leading to higher sediment discharge.
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http://dx.doi.org/10.1038/s41598-020-74980-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581752PMC
October 2020

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.

J Clin Invest 2020 11;130(11):5875-5892

Division of Cancer Therapeutics, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, United Kingdom.

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.
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http://dx.doi.org/10.1172/JCI134132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598076PMC
November 2020

Cryo-EM as a powerful tool for drug discovery.

Bioorg Med Chem Lett 2020 11 2;30(22):127524. Epub 2020 Sep 2.

Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address:

The recent revolution in cryo-EM has produced an explosion of structures at near-atomic or better resolution. This has allowed cryo-EM structures to provide visualization of bound small-molecule ligands in the macromolecules, and these new structures have provided unprecedented insights into the molecular mechanisms of complex biochemical processes. They have also had a profound impact on drug discovery, defining the binding modes and mechanisms of action of well-known drugs as well as driving the design and development of new compounds. This review will summarize and highlight some of these structures. Most excitingly, the latest cryo-EM technology has produced structures at 1.2 Å resolution, further solidifying cryo-EM as a powerful tool for drug discovery. Therefore, cryo-EM will play an ever-increasing role in drug discovery in the coming years.
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http://dx.doi.org/10.1016/j.bmcl.2020.127524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467112PMC
November 2020

(p)ppGpp and c-di-AMP Homeostasis Is Controlled by CbpB in Listeria monocytogenes.

mBio 2020 08 25;11(4). Epub 2020 Aug 25.

Department of Molecular and Cell Biology, University of California, Berkeley, California, USA

The facultative intracellular pathogen , like many related , uses the nucleotide second messenger cyclic di-AMP (c-di-AMP) to adapt to changes in nutrient availability, osmotic stress, and the presence of cell wall-acting antibiotics. In rich medium, c-di-AMP is essential; however, mutations in , the gene encoding c-di-AMP binding protein B, suppress essentiality. In this study, we identified that the reason for -dependent essentiality is through induction of the stringent response by RelA. RelA is a bifunctional RelA/SpoT homolog (RSH) that modulates levels of (p)ppGpp, a secondary messenger that orchestrates the stringent response through multiple allosteric interactions. We performed a forward genetic suppressor screen on bacteria lacking c-di-AMP to identify genomic mutations that rescued growth while was constitutively expressed and identified mutations in the synthetase domain of RelA. The synthetase domain of RelA was also identified as an interacting partner of CbpB in a yeast-2-hybrid screen. Biochemical analyses confirmed that free CbpB activates RelA while c-di-AMP inhibits its activation. We solved the crystal structure of CbpB bound and unbound to c-di-AMP and provide insight into the region important for c-di-AMP binding and RelA activation. The results of this study show that CbpB completes a homeostatic regulatory circuit between c-di-AMP and (p)ppGpp in Bacteria must efficiently maintain homeostasis of essential molecules to survive in the environment. We found that the levels of c-di-AMP and (p)ppGpp, two nucleotide second messengers that are highly conserved throughout the microbial world, coexist in a homeostatic loop in the facultative intracellular pathogen Here, we found that cyclic di-AMP binding protein B (CbpB) acts as a c-di-AMP sensor that promotes the synthesis of (p)ppGpp by binding to RelA when c-di-AMP levels are low. Addition of c-di-AMP prevented RelA activation by binding and sequestering CbpB. Previous studies showed that (p)ppGpp binds and inhibits c-di-AMP phosphodiesterases, resulting in an increase in c-di-AMP. This pathway is controlled via direct enzymatic regulation and indicates an additional mechanism of ribosome-independent stringent activation.
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http://dx.doi.org/10.1128/mBio.01625-20DOI Listing
August 2020

Brassinosteroid-Activated BRI1-EMS-SUPPRESSOR 1 Inhibits Flavonoid Biosynthesis and Coordinates Growth and UV-B Stress Responses in Plants.

Plant Cell 2020 10 13;32(10):3224-3239. Epub 2020 Aug 13.

National Key Laboratory of Plant Molecular Genetics (NKLPMG), CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology (SIPPE), Chinese Academy of Sciences, 200032 Shanghai, People's Republic of China

UV-B light is a potential stress factor in plants, but how plants coordinate growth and UV-B stress responses is not well understood. Here, we report that brassinosteroid (BR) signaling inhibits UV-B stress responses in Arabidopsis () and various crops by controlling flavonol biosynthesis. We further demonstrate that BRI1-EMS-SUPPRESSOR 1 (BES1) mediates the tradeoff between plant growth and UV-B defense responses. BES1, a master transcription factor involved in BR signaling, represses the expression of transcription factor genes , , and , which activate flavonol biosynthesis. BES1 directly binds to the promoters of these in a BR-enhanced manner to repress their expression, thereby reducing flavonol accumulation. However, exposure to broadband UV-B down-regulates expression, thus promoting flavonol accumulation. These findings demonstrate that BR-activated BES1 not only promotes growth but also inhibits flavonoid biosynthesis. UV-B stress suppresses the expression of to allocate energy to flavonoid biosynthesis and UV-B stress responses, allowing plants to switch from growth to UV-B stress responses in a timely manner.
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http://dx.doi.org/10.1105/tpc.20.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534464PMC
October 2020

Studies with recombinant U7 snRNP demonstrate that CPSF73 is both an endonuclease and a 5'-3' exonuclease.

RNA 2020 10 17;26(10):1345-1359. Epub 2020 Jun 17.

Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

Metazoan replication-dependent histone pre-mRNAs are cleaved at the 3' end by U7 snRNP, an RNA-guided endonuclease that contains U7 snRNA, seven proteins of the Sm ring, FLASH, and four polyadenylation factors: symplekin, CPSF73, CPSF100, and CstF64. A fully recombinant U7 snRNP was recently reconstituted from all 13 components for functional and structural studies and shown to accurately cleave histone pre-mRNAs. Here, we analyzed the activity of recombinant U7 snRNP in more detail. We demonstrate that in addition to cleaving histone pre-mRNAs endonucleolytically, reconstituted U7 snRNP acts as a 5'-3' exonuclease that degrades the downstream product generated from histone pre-mRNAs as a result of the endonucleolytic cleavage. Surprisingly, recombinant U7 snRNP also acts as an endonuclease on single-stranded DNA substrates. All these activities depend on the ability of U7 snRNA to base-pair with the substrate and on the presence of the amino-terminal domain (NTD) of symplekin in either or , and are abolished by mutations within the catalytic center of CPSF73, or by binding of the NTD to the SSU72 phosphatase of RNA polymerase II. Altogether, our results demonstrate that recombinant U7 snRNP functionally mimics its endogenous counterpart and provide evidence that CPSF73 is both an endonuclease and a 5'-3' exonuclease, consistent with the activity of other members of the β-CASP family. Our results also raise the intriguing possibility that CPSF73 may be involved in some aspects of DNA metabolism in vivo.
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http://dx.doi.org/10.1261/rna.076273.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491329PMC
October 2020
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