Publications by authors named "Fudong Li"

90 Publications

Mucosal microbial microenvironment in early gastric neoplasia and non-neoplastic gastric disease.

J Gastroenterol Hepatol 2021 Jun 5. Epub 2021 Jun 5.

Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China.

Background And Aim: The biological characterization of microbial environment in early gastric cancer (EGC), other than Helicobacter pylori, is limited. This study aimed to explore the microbial microenvironment in chronic gastritis (CG), fundic gland polyps (FGPs), low-grade intraepithelial neoplasia (LGIN) and EGC.

Methods: 16S-rRNA gene sequencing and bioinformatic analysis were performed on 63 individuals with 252 mucosal biopsies or endoscopic submucosal dissection margin samples from endoscopy.

Results: The microbiota in gastric LGIN functions analogously to EGC in terms of functional prediction. Neoplastic lesions showed a significant difference to CG or FGPs in beta diversity of the microbiota. Bacteria genera including Paracoccus, Blautia, Barnesiella, Lactobacillus, Thauera, Collinsella were significantly enriched in gastric neoplastic mucosa (LGIN and EGC) compared to non-neoplastic tissues (CG and FGPs). Whilst Pseudomonas and Kingella were depleted in neoplastic tissues. FGPs showed a distinctive microbial network system that negatively interacted with Helicobacter.

Conclusions: In terms of the mucosal microbial microenvironment, gastric LGIN and EGC showed no significant difference as early neoplastic lesions. We observed a coordinated microbial microenvironment that correlated negatively with Helicobacter.
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http://dx.doi.org/10.1111/jgh.15565DOI Listing
June 2021

Long noncoding RNA AC092155 facilitates osteogenic differentiation of adipose-derived stem cells through the miR-143-3p/STMN1 axis.

J Gene Med 2021 May 15:e3363. Epub 2021 May 15.

Department of Orthopedic Surgery, Jinling Hospital, Nanjing University, Nanjing, China.

Background: Numerous studies have demonstrated that long noncoding RNAs (lncRNAs) induce osteogenesis in adipose-derived stem cells (ADSCs). This study aimed to explore the role of lncRNAs AC092155 in promoting osteogenic differentiation of ADSCs.

Methods: MicroRNA (miRNA) and lncRNA sequencing were performed in ADSCs that underwent normal or osteogenic induction. Differentially expressed miRNAs and lncRNAs were identified using R software. The relative expression levels of lncRNA AC092155, miR-143-3p, and STMN1 during the process of osteogenic induction were determined by real-time polymerase chain reaction (RT-PCR). ADSCs were then transfected with agomiR-143-3p and pcDNA3.1-sh-lncRNA AC092155. Alkaline phosphatase (ALP) and alizarin red staining (ARS) were used to confirm the regulatory function of the lncRNA AC092155/miR-143-3p/STMN1 axis in osteogenic differentiation of ADSCs.

Results: lncRNA AC092155 was significantly upregulated in ADSCs following induction in the osteogenic medium. lncRNA AC092155 and STMN1 mimics increase the markers of osteogenic differentiation in the early and late phases, which was reflected in increased ALP activity as well as the higher deposition of calcium nodules. An miR-143-3p mimic showed the opposite effect. Luciferase reporter gene analysis demonstrated that lncRNA AC092155 directly targets miR-143-3p. Moreover, the lncRNA AC092155/miR-143-3p/STMN1 regulatory axis was found to activate the Wnt/β-catenin signaling pathway.

Conclusions: lncRNA AC092155 contributes to the osteogenic differentiation of ADSCs. The lncRNA AC092155/miR-143-3p/STMN1 axis may be a new therapeutic target for bone-related diseases.
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http://dx.doi.org/10.1002/jgm.3363DOI Listing
May 2021

Ulinastatin Ameliorates IL-1-Induced Cell Dysfunction in Human Nucleus Pulposus Cells via Nrf2/NF-B Pathway.

Oxid Med Cell Longev 2021 21;2021:5558687. Epub 2021 Apr 21.

Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University (Second Military Medical University), No. 415 Fengyang Road, Shanghai 200003, China.

Low back pain (LBP) has been a wide public health concern worldwide. Among the pathogenic factors, intervertebral disc degeneration (IDD) has been one of the primary contributors to LBP. IDD correlates closely with inflammatory response and oxidative stress, involving a variety of inflammation-related cytokines, such as interleukin 1 beta (IL-1), which could result in local inflammatory environment. Ulinastatin (UTI) is a kind of acidic protein extracted from human urine, which inhibits the release of tumor necrosis factor alpha (TNF-) and other inflammatory factors to protect organs from inflammatory damage. However, whether this protective effect of UTI on human nucleus pulposus (NP) exists, and how UTI affects the biological behaviors of human NP cells during IDD remain elusive. In this current study, we revealed that UTI could improve the viability of NP cells and promote the proliferation of NP cells. Additionally, UTI could protect human NP cells via ameliorating IL-1-induced apoptosis, inflammatory response, oxidative stress, and extracellular matrix (ECM) degradation. Molecular mechanism analysis suggested that the protective effect from UTI on IL-1-treated NP cells were through activating nuclear factor- (erythroid-derived 2-) like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and the suppression of NF-B signaling pathway. Therefore, UTI may be a promising therapeutic medicine to ameliorate IDD.
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http://dx.doi.org/10.1155/2021/5558687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084647PMC
May 2021

PD-L1 Improves Motor Function and Alleviates Neuropathic Pain in Male Mice After Spinal Cord Injury by Inhibiting MAPK Pathway.

Front Immunol 2021 15;12:670646. Epub 2021 Apr 15.

Department of Orthopedic Surgery, Spine Center, Changzheng Hospital, Naval Medical University, Shanghai, China.

Background: Traumatic spinal cord injury (SCI) causes severe motor dysfunction and persistent central neuropathic pain (Nep), which has not yet been effectively cured. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and contributes to the immune-suppressive in tumor microenvironment. However, the role of PD-L1 in regulating inflammatory response and Nep after SCI remains unclear. A growing amount of researches have begun to investigate the effect of PD-L1 on macrophages and microglia in recent years. Considering the pivotal role of macrophages/microglia in the inflammatory response after SCI, we proposed the hypothesis that PD-L1 improved the recovery of locomotor and sensory functions after SCI through regulating macrophages and microglia.

Methods: The mice SCI model was established to determine the changes in expression patterns of PD-L1. Meanwhile, we constructed PD-L1 knockout mice to observe differences in functional recovery and phenotypes of macrophages/microglia post-SCI.

Results: In present study, PD-L1 was significantly upregulated after SCI and highly expressed on macrophages/microglia at the injury epicenter. PD-L1 knockout (KO) mice showed worse locomotor recovery and more serious pathological pain compared with wild-type (WT) mice. Furthermore, deletion of PD-L1 significantly increased the polarization of M1-like macrophages/microglia. Mechanistic analysis revealed that PD-L1 may improve functional outcomes following SCI by inhibiting phosphorylation of p38 and ERK1/2.

Conclusions: Our observations implicate the involvement of PD-L1 in recovery of SCI and provide a new treatment strategy for the prevention and treatment of this traumatic condition.
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http://dx.doi.org/10.3389/fimmu.2021.670646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081847PMC
April 2021

Bleeding after endoscopic resection between direct oral anticoagulants or warfarin: Systematic review and meta-analysis.

J Gastroenterol Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China.

Background And Aim: Oral anticoagulants are risk factors for post-endoscopic resection bleeding. We aimed to conduct a systematic review and meta-analysis for the risks of post-procedural bleeding (PPB) for direct oral anticoagulants (DOACs) and warfarin following endoscopic resection.

Methods: Two independent reviewers searched PubMed, Web of Science, Embase, and Cochrane Library. The Newcastle-Ottawa Scale score was used to assess the quality of the studies, the pooled odds ratio (OR) to present PPB results, and the funnel plots to assess publication bias. The Higgins I statistic was employed to determine the variation across studies due to heterogeneity.

Results: We reviewed 30 articles. PPB occurred in 586 patients on DOACs and 1782 on warfarin. The patients on DOACs had a significantly lower overall risk of PPB compared with those on warfarin (OR, 0.867, 95% confidence interval, 0.771-0.975; P = 0.017, I  = 1.6%). Cumulative meta-analysis showed that the PPB rate of DOACs has the trend to be lower than that of warfarin with publication year and sample size. For the subgroup of endoscopic submucosal dissection, the PPB of DOACs was significantly lower than that of warfarin (OR, 0.786; 95% confidence interval, 0.633-0.976; P = 0.029, I  = 0%). No significant difference was observed between DOACs and warfarin for anticoagulant strategies, endoscopic procedures, and lesion location.

Conclusions: Compared with warfarin, DOACs have the possibility to significantly decrease the risk of PPB following endoscopic resection, especially for endoscopic submucosal dissection.
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http://dx.doi.org/10.1111/jgh.15527DOI Listing
April 2021

Intelligent fault diagnosis of machines with small & imbalanced data: A state-of-the-art review and possible extensions.

ISA Trans 2021 Mar 8. Epub 2021 Mar 8.

School of Mechanical Science and Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China; Dongfeng Liuzhou Motor Co., Ltd., Liuzhou 545005, China.

The research on intelligent fault diagnosis has yielded remarkable achievements based on artificial intelligence-related technologies. In engineering scenarios, machines usually work in a normal condition, which means limited fault data can be collected. Intelligent fault diagnosis with small & imbalanced data (S&I-IFD), which refers to build intelligent diagnosis models using limited machine faulty samples to achieve accurate fault identification, has been attracting the attention of researchers. Nowadays, the research on S&I-IFD has achieved fruitful results, but a review of the latest achievements is still lacking, and the future research directions are not clear enough. To address this, we review the research results on S&I-IFD and provides some future perspectives in this paper. The existing research results are divided into three categories: the data augmentation-based, the feature learning-based, and the classifier design-based. Data augmentation-based strategy improves the performance of diagnosis models by augmenting training data. Feature learning-based strategy identifies faults accurately by extracting features from small & imbalanced data. Classifier design-based strategy achieves high diagnosis accuracy by constructing classifiers suitable for small & imbalanced data. Finally, this paper points out the research challenges faced by S&I-IFD and provides some directions that may bring breakthroughs, including meta-learning and zero-shot learning.
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http://dx.doi.org/10.1016/j.isatra.2021.02.042DOI Listing
March 2021

Mild to Severe Depressive Symptoms in Elderly Stroke Survivors and Its Associated Factors: Evidence From a Cross-Sectional Study in Zhejiang Province, China.

Front Psychiatry 2020 25;11:551621. Epub 2021 Feb 25.

Director Office, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.

The objective of the study is to explore the prevalence of mild to severe depressive symptoms in elderly stroke survivors and its associated factors. We did data analyses of 335 elders with stroke history. Data were collected in a survey conducted between 2014 and 2015, among permanent residents aged 60 and older in Zhejiang Province, China. Prevalence of mild to severe depressive symptoms among stroke survivors were calculated, and univariate analyses and multilevel logistic regression were used to explore its associated factors. Prevalence of mild to severe depressive symptoms was 22.09% (95% CI: 17.65-26.53%) in elders with stroke history, more than twice compared to their counterparts not suffering stroke (9.77%, < 0.001). In multilevel logistic regression, we found that elderly stroke survivors who were illiterate (OR = 2.33, = 0.008), or had limitation in activities of daily living (OR = 3.04, = 0.001) were more likely to be present with mild to severe depressive symptoms, respectively, while those with more fresh vegetable consumption were at lower odds (OR = 0.82, = 0.047). Prevalence of mild to severe depressive symptoms was high in elderly stroke survivors. Targeted screening might be needed for those being illiterate, disabled in activities of daily living, and having little consumption of fresh vegetable. The association between fresh vegetable consumption and depressive symptom in stroke patients calls for further research.
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http://dx.doi.org/10.3389/fpsyt.2020.551621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947299PMC
February 2021

Structural and biochemical insights into the recognition of RNA helicase CGH-1 by CAR-1 in C. elegans.

Biochem Biophys Res Commun 2021 Apr 3;549:135-142. Epub 2021 Mar 3.

Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, PR China; Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science & Technology of China, Hefei, PR China. Electronic address:

A protein-RNA complex containing the RNA helicase CGH-1 and a germline specific RNA-binding protein CAR-1 is involved in various aspects of function in C. elegans. However, the structural basis for the assembly of this protein complex remains unclear. Here, we elucidate the molecular basis of the recognition of CGH-1 by CAR-1. Additionally, we found that the ATPase activity of CGH-1 is stimulated by NTL-1a MIF4G domain in vitro. Furthermore, we determined the structures of the two RecA-like domains of CGH-1 by X-ray crystallography at resolutions of 1.85 and 2.40 Å, respectively. Structural and biochemical approaches revealed a bipartite interface between CGH-1 RecA2 and the FDF-TFG motif of CAR-1. NMR and structure-based mutations in CGH-1 RecA2 or CAR-1 attenuated or disrupted CGH-1 binding to CAR-1, assessed by ITC and GST-pulldown in vitro. These findings provide insights into a conserved mechanism in the recognition of CGH-1 by CAR-1. Together, our data provide the missing physical links in understanding the assembly and function of CGH-1 and CAR-1 in C. elegans.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.119DOI Listing
April 2021

Does aluminum exposure affect cognitive function? a comparative cross-sectional study.

PLoS One 2021 16;16(2):e0246560. Epub 2021 Feb 16.

Department of Public Health Surveillance and Advisory, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, China.

Objectives: This study assessed the cognitive function of aluminum-exposed participants from an alum mining zone, compared them with unexposed subjects, and aimed to elucidate the effect of aluminum exposure on cognition.

Design: This was a comparative cross-sectional study. Univariate analyses were used to assess the differences between the aluminum-exposed and unexposed groups. Binary logistic regression models were applied to analyze the effect of aluminum exposure.

Setting: The aluminum-exposed participants were included from an alum mining zone and the unexposed subjects were residents from another district without alum-mine-related factories.

Participants: We included 539 aluminum-exposed participants (254 men, 285 women) and 1720 unexposed participants (692 men, 1028 women).

Results: The mean cognition score on Mini-Mental State Examination was 21.34 (± 6.81) for aluminum-exposed participants. The exposed group had 6.77 times (95% confidence interval, 5.09-9.00) more risk of cognitive impairment than the unexposed group, after adjusting for age, sex, and educational level. No statistically significant association was found between exposure duration and cognition.

Conclusions: This study demonstrated a significant association between aluminum exposure and lower cognitive function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246560PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886175PMC
February 2021

Zinc Finger Protein SALL4 Functions through an AT-Rich Motif to Regulate Gene Expression.

Cell Rep 2021 01;34(1):108574

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address:

The zinc finger transcription factor SALL4 is highly expressed in embryonic stem cells, downregulated in most adult tissues, but reactivated in many aggressive cancers. This unique expression pattern makes SALL4 an attractive therapeutic target. However, whether SALL4 binds DNA directly to regulate gene expression is unclear, and many of its targets in cancer cells remain elusive. Here, through an unbiased screen of protein binding microarray (PBM) and cleavage under targets and release using nuclease (CUT&RUN) experiments, we identify and validate the DNA binding domain of SALL4 and its consensus binding sequence. Combined with RNA sequencing (RNA-seq) analyses after SALL4 knockdown, we discover hundreds of new SALL4 target genes that it directly regulates in aggressive liver cancer cells, including genes encoding a family of histone 3 lysine 9-specific demethylases (KDMs). Taken together, these results elucidate the mechanism of SALL4 DNA binding and reveal pathways and molecules to target in SALL4-dependent tumors.
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http://dx.doi.org/10.1016/j.celrep.2020.108574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197658PMC
January 2021

Esophageal intramural squamous cell carcinomas presenting as subepithelial lesions removed by endoscopic submucosal dissection: Two case reports.

Medicine (Baltimore) 2020 Nov;99(45):e21850

Department of Gastroenterology, The First Hospital of Jilin University, ChangChun, Jilin, China.

Introduction: Esophageal subepithelial lesions (SELs) are rare, and the majority of them are benign. SELs are often covered with normal mucosa, thereby resulting in some malignant SELs to be easily missed or misdiagnosed. We report 2 cases of esophageal intramural squamous cell carcinomas (SCCs) that presented as SELs and were endoscopically removed.

Patient Concerns: Case 1 is a 63-year-old man with abdominal distension; case 2 is a 65-year-old man with increasing dysphagia for 2 months.

Diagnosis: In case 1, endoscopy showed a 1.5-cm mucosal eminence with normal overlying mucosa. Endoscopic ultrasound (EUS) revealed that it might be derived from the muscularis mucosa or submucosa. In case 2, endoscopy revealed a 1.2-cm hemispherical lesion covered with smooth mucosa. Furthermore, EUS revealed that this lesion might be derived from the submucosa.

Interventions: In both cases, the lesions were removed by endoscopic submucosal dissection (ESD). Pathological examination revealed esophageal SCC nests with intramural growth patterns.

Outcomes: The first patient underwent postoperative radiotherapy, whereas the second patient did not receive any additional treatment. Both patients agreed to regular follow-up, and no tumor recurrence or metastasis was observed.

Conclusion: First, not all esophageal SELs are benign, and a small number of SELs can be malignant. Second, these cases illustrate the value of newer endoscopic techniques, especially ESD. Thus, it is important to be alert when visualizing the esophagus for the possibility of a subtle SEL so that further evaluation and treatment, if necessary, can be undertaken, ideally with a less invasive approach afforded by ESD.
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http://dx.doi.org/10.1097/MD.0000000000021850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647628PMC
November 2020

ERH facilitates microRNA maturation through the interaction with the N-terminus of DGCR8.

Nucleic Acids Res 2020 11;48(19):11097-11112

Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea.

The microprocessor complex cleaves the primary transcript of microRNA (pri-miRNA) to initiate miRNA maturation. Microprocessor is known to consist of RNase III DROSHA and dsRNA-binding DGCR8. Here, we identify Enhancer of Rudimentary Homolog (ERH) as a new component of Microprocessor. Through a crystal structure and biochemical experiments, we reveal that ERH uses its hydrophobic groove to bind to a conserved region in the N-terminus of DGCR8, in a 2:2 stoichiometry. Knock-down of ERH or deletion of the DGCR8 N-terminus results in a reduced processing of suboptimal pri-miRNAs in polycistronic miRNA clusters. ERH increases the processing of suboptimal pri-miR-451 in a manner dependent on its neighboring pri-miR-144. Thus, the ERH dimer may mediate 'cluster assistance' in which Microprocessor is loaded onto a poor substrate with help from a high-affinity substrate in the same cluster. Our study reveals a role of ERH in the miRNA biogenesis pathway.
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http://dx.doi.org/10.1093/nar/gkaa827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641749PMC
November 2020

Blood pressure and cognitive decline over the course of 2 years in elderly people: a community-based prospective cohort study.

Aging Clin Exp Res 2020 Sep 26. Epub 2020 Sep 26.

Department of Public Health Surveillance and Advisory, Zhejiang Provincial Center for Disease Control and Prevention, No. 3399, Binsheng Rd., Binjiang District, Hangzhou, Zhejiang, People's Republic of China.

Background: Numerous studies have shown a significant association between blood pressure (BP) and cognition, but little is known about the effect of BP on the rate of cognitive decline.

Aims: To investigate the relationship between blood pressure and the subsequent rate of cognitive decline in elderly people.

Methods: Based on a prospective cohort that has been followed since 2014, we collected baseline blood pressures and other covariates in 7874 Chinese individuals aged 60 years or older, and followed their cognitive change using the Mini-Mental State Examination (MMSE) until Dec 31, 2016. Linear mixed-effects models were used to measure changes in MMSE scores over time in relation to blood pressure values, and in addition to the covariates, we included random effects for intercepts and slopes.

Results: In the non-hypertension group, we observed that faster cognitive decline was associated with higher systolic blood pressure, lower diastolic blood pressure, lower mean arterial pressure, and higher pulse pressure. In the hypertension group, lower diastolic blood pressure, lower mean arterial pressure, and higher pulse pressure were associated with faster cognitive decline, but not systolic blood pressure.

Conclusion: Higher systolic blood pressure, lower diastolic blood pressure, lower mean arterial pressure, and higher pulse pressure accelerate the subsequent rate of cognitive decline in elderly people. The results of this study may help improve blood-pressure control strategies to prevent cognitive decline.
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http://dx.doi.org/10.1007/s40520-020-01717-7DOI Listing
September 2020

Risk of severe coronavirus disease in imported and secondary cases in Zhejiang province, China.

J Public Health (Oxf) 2021 04;43(1):35-41

Department of Public Health Surveillance and Advisory, Zhejiang Provincial Center for Disease Control and Prevention, Zhejiang, China 310051.

Background: To our knowledge, no previous studies have focused on determining whether the virulence and case fatality rate of the severe acute respiratory coronavirus 2 (SARS-CoV-2) decreases as the virus continues to spread. Hence, our aim was to retrospectively explore the differences in the risk of severe or critical COVID-19 among imported, secondary and tertiary cases in Zhejiang, China.

Methods: We categorized COVID-19 cases reported by hospitals in Zhejiang as first-, second- and third-generation cases. Univariate and multivariate logistic regression analyses were performed to compare disease severity and case generation.

Results: Of 1187 COVID-19 cases, 227 (19.1%, 95% CI: 16.9-21.4) manifested severe or critical illness. The adjusted risk difference for severe or critical illness was lower for second- (odds ratio (OR) = 0.84, 95% confidence interval (CI): 0.52-1.36) and third-generation (OR = 0.55, 95% CI: 0.37-0.83) cases than for first-generation cases. Compared with hospitalized patients, cases identified at centralized isolation locations (OR = 0.62, 95% CI: 0.40-0.97) and those identified through active search or gateway screening (OR = 0.28, 95% CI: 0.08-1.04) were at a lower risk of severe or critical illness.

Conclusions: Second- and third-generation cases of COVID-19 have a lower risk of developing severe or critical illness than first-generation cases.
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http://dx.doi.org/10.1093/pubmed/fdaa158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543419PMC
April 2021

Impact of Air Pollution on Cognitive Impairment in Older People: A Cohort Study in Rural and Suburban China.

J Alzheimers Dis 2020 ;77(4):1671-1679

Faculty of Education, Health and Wellbeing, University of Wolverhampton, UK.

Background: The impact of air pollution on cognitive impairment in older people has not been fully understood. It is unclear which air pollutants are the culprit.

Objective: We assessed the associations of six air pollutants and air quality index (AQI) with cognitive impairment.

Methods: We examined 7,311 participants aged ≥60 years from the ZJMPHS cohort in China. They were interviewed for baseline socio-demographic and disease risk factors in 2014, and re-interviewed in 2015 and 2016, respectively. The presence of cognitive impairment was determined by the Chinese version of the Mini-Mental State Examination. Daily area-level data monitored for air pollution during 2013-2015 was then examined for associations with cognitive impairment in logistic regression models.

Results: Over the two years follow-up, 1,652 participants developed cognitive impairment, of which 917 were severe cases. Continuous air pollution data showed the risk of cognitive impairment increased with exposure to PM2.5 (fully adjusted odds ratio [aOR] 1.04, 95% CI 1.01-1.08), PM10 (1.03, 1.001-1.06), and SO2 (1.04, 1.01-1.08), but not with NO2, CO, O3, and AQI. Categorized data analysis for low, middle, and high level exposure demonstrated that the aOR increased with PM2.5 and AQI, somehow with PM10 and CO, but not significantly with SO2 and NO2, and decreased with O3. The patterns for these associations with severe cognitive impairment were stronger.

Conclusion: Lowering PM2.5, PM10, SO2, and CO level could reduce the risk of cognitive impairment in older Chinese. Strategies to target most important air pollutants should be an integral component of cognitive interventions.
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http://dx.doi.org/10.3233/JAD-200587DOI Listing
January 2020

Conformational Selection in Ligand Recognition by the First Tudor Domain of PHF20L1.

J Phys Chem Lett 2020 Sep 9;11(18):7932-7938. Epub 2020 Sep 9.

Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, the First Affiliated Hospital & School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P.R. China.

The first Tudor domain (Tudor1) of PHF20L1 recognizes (non)histone methylation to play versatile roles. However, the underlying ligand-recognition mechanism remains unknown as a closed state revealed in the free-form structure. NMR relaxation dispersion and molecular dynamics simulations suggest a pre-existing low-population conformation with a remarkable rearrangement of aromatic cage residues of PHF20L1 Tudor1. Such an open-form conformation is utilized to recognize lysine 142 methylated DNMT1, a cosolvent, and an NMR fragment screening hit, as revealed by the complex crystal structures. Intriguingly, the ligand binding capacity was enhanced by mutation that tunes up the open-state population only. The recognition of DNMT1 by PHF20L1 was further validated in cancer cells. This conformational selection mechanism will enable the discovery of small molecule inhibitors against the seemingly "undruggable" PHF20L1 Tudor1.
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http://dx.doi.org/10.1021/acs.jpclett.0c02039DOI Listing
September 2020

Repurposing Low-Molecular-Weight Drugs against the Main Protease of Severe Acute Respiratory Syndrome Coronavirus 2.

J Phys Chem Lett 2020 Sep 20;11(17):7267-7272. Epub 2020 Aug 20.

Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Huangshan Road, Hefei, Anhui 230027, P.R. China.

The coronavirus disease pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. As low-molecular-weight drugs have high potential to completely match interactions with essential SARS-CoV-2 targets, we propose a strategy to identify such drugs using the fragment-based approach. Herein, using ligand- and protein-observed fragment screening approaches, we identified niacin and hit binding to the catalytic pocket of the main protease (M) of SARS-CoV-2, thereby modestly inhibiting the enzymatic activity of M. We further searched for low-molecular-weight drugs containing niacin or hit pharmacophores with enhanced inhibiting activity, e.g., carmofur, bendamustine, triclabendazole, emedastine, and omeprazole, in which omeprazole is the only one binding to the C-terminal domain of SARS-CoV-2 M. Our study demonstrates that the fragment-based approach is a feasible strategy for identifying low-molecular-weight drugs against the SARS-CoV-2 and other potential targets lacking specific drugs.
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http://dx.doi.org/10.1021/acs.jpclett.0c01894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441750PMC
September 2020

Intelligent Impulse Finder: A boosting multi-kernel learning network using raw data for mechanical fault identification in big data era.

ISA Trans 2020 Dec 1;107:402-414. Epub 2020 Aug 1.

State Key Laboratory for Manufacturing and Systems Engineering, Xi'an Jiaotong University, Xi'an 710049, PR China.

Nowadays, most intelligent diagnosis methods focus on fault classification and the discriminative knowledge is unknown due to the 'black box' characteristic. However, impulse responses in vibration signals, which is important sign to determine whether mechanical equipment is faulty, are rarely studied under intelligent methods since their recognition is both difficult and time-consuming, especially mixed with noise. Aiming at these problems, a novel impulse recognition method was proposed to capture them from raw mechanical data. Firstly, a single-kernel convolutional neural network is proposed as weak classifier to learn discriminative information from raw data. Then, a coarse-to-fine search is proposed to locate position of impulse response. Finally, the boosting algorithm is used to ensemble several proposed weak classifiers for final output. Vibration signals of bearings with two different faults are utilized to validate the proposed model. The results prove that the proposed approach obtain higher accuracy compared with traditional Laplace wavelet method. Moreover, the extracted kernel functions reveal new knowledge about characteristics of impulse responses, which significantly differs from traditional hypothesis and sheds a light on improvement of relevant approaches.
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http://dx.doi.org/10.1016/j.isatra.2020.07.039DOI Listing
December 2020

Association of empty nest and group activity with cognitive impairment in Chinese older adults: A cross-sectional study.

Arch Gerontol Geriatr 2020 Sep - Oct;90:104120. Epub 2020 May 21.

Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Binjiang District, Hangzhou 310051, Zhejiang, China. Electronic address:

Objectives: This study explored the associations of empty nest and group activity with cognitive impairment in Chinese older adults.

Materials And Methods: Data were analyzed from 10,349 participants of the second-round survey database of the Zhejiang Ageing and Health Cohort Study aged 60 years and over. Cognitive impairment was assessed by the Mini-Mental State Examination questionnaire. Logistic regression models controlled for an extensive range of potential confounders were generated to examine the associations of empty nest and group activity with cognitive impairment.

Results: No association was found between empty nest and cognitive impairment in total participants. However, when stratified by sex, empty nest women were less likely to have cognitive impairment than non-empty nest women, odds ratio (OR) (95 % confidence interval [CI]) (0.846; 0.721, 0.993). Elders who participated in group activities showed significantly lower odds of cognitive impairment than those who never attended group activities, (0.811; 0.723, 0.910). This association remained significant in the 60-69-years group when further stratified by age, with an OR (95 % CI) of 0.616 (0.514, 0.739).

Conclusions: Empty nesters were not vulnerable to poor cognitive function. Participation in group activities was significantly associated with lower odds of cognitive impairment. Prospective studies are needed to assess the effect of empty nest and group activity on the risk of cognitive impairment.
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http://dx.doi.org/10.1016/j.archger.2020.104120DOI Listing
December 2020

Passive Smoking Exposure in Living Environments Reduces Cognitive Function: A Prospective Cohort Study in Older Adults.

Int J Environ Res Public Health 2020 02 21;17(4). Epub 2020 Feb 21.

Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032, China.

There is currently no consensus regarding the effects of passive smoking exposure on cognitive function in older adults. We evaluated 7000 permanent residents from six regions within Zhejiang Province, China, aged ≥60 years, without cognitive impairment at baseline and during follow-up examinations for two years. The Chinese version of the Mini-Mental State Examination was used to assess the participants' cognitive function. Multivariate regression analyses were carried out to calculate the adjusted relative risks (RRs) as measures of the association between passive smoking exposure and cognitive impairment after adjusting for potential confounders. The results showed an association between passive smoking exposure in the living environment and increased risk of cognitive impairment (RR: 1.16; 95% confidence interval (CI): 1.01-1.35). No dose-response relationship between the cumulative dose of passive smoking exposure (days) and cognitive impairment was observed. The results of stratified analyses suggested a harmful effect of passive smoking exposure on cognitive function in non-smokers (RR: 1.24; 95% CI: 1.06-1.46), but not in smokers (RR: 1.11; 95% CI: 0.71-1.92). Therefore, passive smoking exposure increased the risk of cognitive impairment in older adults, especially non-smokers. More effective measures to restrict smoking in the living environment should be developed and implemented.
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http://dx.doi.org/10.3390/ijerph17041402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068506PMC
February 2020

A Bayesian classification model for discriminating common infectious diseases in Zhejiang province, China.

Medicine (Baltimore) 2020 Feb;99(8):e19218

Zhejiang Provincial Center for Disease Control and Prevention.

To develop a classification model for accurately discriminating common infectious diseases in Zhejiang province, China.Symptoms and signs, abnormal lab test results, epidemiological features, as well as the incidence rates were treated as predictors, and were collected from the published literature and a national surveillance system of infectious disease. A classification model was established using naïve Bayesian classifier. Dataset from historical outbreaks was applied for model validation, while sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC) and M-index were presented.A total of 146 predictors were included in the classification model, for discriminating 25 common infectious diseases. The sensitivity ranged from 44.44% for hepatitis E to 96.67% for measles. The specificity varied from 96.36% for dengue fever to 100% for 5 diseases. The median of total accuracy was 97.41% (range: 93.85%-99.04%). The AUCs exceeded 0.98 in 11 of 12 diseases, except in dengue fever (0.613). The M-index was 0.960 (95%CI 0.941-0.978).A novel classification model was constructed based on Bayesian approach to discriminate common infectious diseases in Zhejiang province, China. After entering symptoms and signs, abnormal lab test results, epidemiological features and city of disease origin, an output list of possible diseases ranked according to the calculated probabilities can be provided. The discrimination performance was reasonably good, making it useful in epidemiological applications.
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http://dx.doi.org/10.1097/MD.0000000000019218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034623PMC
February 2020

Spatial and temporal analysis of severe fever with thrombocytopenia syndrome in Zhejiang Province, China, 2011 - 2015.

J Infect Dev Ctries 2019 01 31;13(1):35-43. Epub 2019 Jan 31.

Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Binjiang District, Hangzhou 310051, Zhejiang, China.

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease first discovered in northeast and central China in 2009, and SFTS cases increased year by year in China. This study aimed to identify the spatial and temporal clusters of SFTS in Zhejiang Province, China.

Methodology: We analyzed the surveillance data of SFTS in Zhejiang Province during 2011 - 2015. Descriptive statistics were used to analyze the general characteristics and overall trend of SFTS. Circular statistic method was utilized to identify the seasonality. Space-time scan analysis was performed to explore the high risk spatio-temporal clusters of SFTS cases at county level.

Results: A total of 194 confirmed SFTS cases were reported in Zhejiang Province during 2011 - 2015. We found a significant increase in overall time trend since 2011. The seasonality was statistically significant (P < 0.001), with a mean date (95% CI) of 21st June (12th ~ 30th in June). Totally 21 (23%) counties reported the occurrence of SFTS, which gradually spread throughout Zhejiang. Three spatio-temporal clusters were detected, with one principle cluster (Daishan County, RR 234.48, June 2013 - November 2015) and two secondary clusters (6 counties, RR 30.73, April - October in 2015; Anji County, RR 373.26, May 2014).

Conclusions: Our results suggested that SFTS has increased and spatially expanded over the past years, with a remarkable seasonality. Three spatio-temporal clusters were identified. These findings are important for the improvement of SFTS surveillance and control strategies.
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http://dx.doi.org/10.3855/jidc.10373DOI Listing
January 2019

Crystal structure of Arabidopsis terminal uridylyl transferase URT1.

Biochem Biophys Res Commun 2020 04 31;524(2):490-496. Epub 2020 Jan 31.

Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui, 230027, China. Electronic address:

3' uridylation is an essential modification associated with coding and noncoding RNA degradation in eukaryotes. In Arabidopsis, HESO1 was first identified as the major nucleotidyl transferase that uridylates most unmethylated miRNAs, and URT1 was later reported to play a redundant but important role in miRNA uridylation when HESO1 is absent. Two enzymes work sequentially and collaboratively to tail different forms of the same miRNAs in vivo. For mRNA, however, URT1 becomes the main enzyme to uridylate the majority of mRNA and repairs their deadenylated ends to restore the binding site for Poly(A) Binding Protein (PABP). HESO1, on the other hand, targets mostly the mRNAs with very short oligo(A) tails and fails in fulfilling the same task. To understand the structural basis these two functional homologues possess for their different substrate preferences and catalytic behaviors, we first determined the crystal structures of URT1 in the absence and presence of UTP. Our structures, together with functional assay and sequence analysis, indicated that URT1 has a conserved UTP-recognition mechanism analogue to the terminal uridylyl transferases from other species whereas HESO1 may evolve separately to recognize UTP in a different way. Moreover, URT1 N552 may be an important residue in interacting with 3' nucleotide of RNA substrate. The URT1 structure we determined represents the first structure of uridylyl transferase from plants, shedding light on the mechanisms of URT1/HESO1-dependent RNA metabolism.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.124DOI Listing
April 2020

The utilization status of neoadjuvant chemotherapy in muscle-invasive bladder cancer: a systematic review and meta-analysis.

Minerva Urol Nephrol 2021 Apr 7;73(2):144-153. Epub 2020 Jan 7.

Key Laboratory of Gansu Province for Urological Diseases, Institute of Urology, Lanzhou University Second Hospital, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu Province, China -

Introduction: To give a comprehensive depiction of the utilization status of neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC) worldwide.

Evidence Acquisition: Potential relevant research papers of Pubmed, Embase, Web of Science, and the Cochrane Library were reviewed to identify eligible studies. Primary outcomes of this meta-analysis were utilization rate of NAC and its utility distribution in different genders, races, ages, countries and temporal trends. The utilization rates of NAC were calculated as 'Proportion (s)' with 95% confidence intervals (CIs) and pooled estimates were calculated by using a random-effect model.

Evidence Synthesis: A total of thirteen studies and 35,738 patients were included. The total proportion of NAC applied in MIBC populations prior to radical cystectomy (RC) was 17.2% (95% CI: 12.5-21.9%, I=99.7%). The comparative analyses showed there were no significant differences existing in different genders or races on NAC utilization rates. In terms of age distribution, <60 age group conferred higher utilization rate of NAC than the older (OR=1.919, 95% CI: 1.671-2.202, P=0.0001). As for regional distribution, our meta-analysis showed that Japan (Proportion: 44.0%, 95% CI: 6.5-81.5%, I=99.6%) and Sweden (37.9%, 95% CI: 34.9-40.8%) were the top two leading countries which contributed to the most frequent application of NAC. In respect of pathologic responses after NAC, complete, partial and down-staged pathologic responses were achieved in 16.6% (95% CI: 7.4-25.9%, I=89.7%), 14.6% (95% CI: 0.8-28.5%, I=89.7%) and 45.0% (95% CI: 17.8-72.2%, I=98.8%) patients, respectively.

Conclusions: The present study shows the low utilization rate of NAC in MIBC patients. Standardization of the treatment modality of MIBC and promotion of guidelines might be necessary to expedite the adoption of NAC in near future.
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http://dx.doi.org/10.23736/S0393-2249.19.03648-8DOI Listing
April 2021

SAM-VI riboswitch structure and signature for ligand discrimination.

Nat Commun 2019 12 16;10(1):5728. Epub 2019 Dec 16.

Life Sciences Institute, Zhejiang University, 310058, Hangzhou, Zhejiang, China.

Riboswitches are metabolite-sensing, conserved domains located in non-coding regions of mRNA that are central to regulation of gene expression. Here we report the first three-dimensional structure of the recently discovered S-adenosyl-L-methionine responsive SAM-VI riboswitch. SAM-VI adopts a unique fold and ligand pocket that are distinct from all other known SAM riboswitch classes. The ligand binds to the junctional region with its adenine tightly intercalated and Hoogsteen base-paired. Furthermore, we reveal the ligand discrimination mode of SAM-VI by additional X-ray structures of this riboswitch bound to S-adenosyl-L-homocysteine and a synthetic ligand mimic, in combination with isothermal titration calorimetry and fluorescence spectroscopy to explore binding thermodynamics and kinetics. The structure is further evaluated by analysis of ligand binding to SAM-VI mutants. It thus provides a thorough basis for developing synthetic SAM cofactors for applications in chemical and synthetic RNA biology.
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http://dx.doi.org/10.1038/s41467-019-13600-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914780PMC
December 2019

Structural Insights into ceNAP1 Chaperoning Activity toward ceH2A-H2B.

Structure 2019 12 22;27(12):1798-1810.e3. Epub 2019 Oct 22.

Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China. Electronic address:

In eukaryotes, nucleosome assembly is crucial for genome integrity. The histone chaperone NAP1 plays an important role in histone folding, storage, and transport, as well as histone exchange and nucleosome assembly. At present, the molecular basis of these activities is not fully understood. We have solved high-resolution crystal structures of Caenorhabditis elegans NAP1 (ceNAP1) in complex with its cognate substrates: the C. elegans H2A-H2B dimer (ceH2A-H2B) and the H2A.Z-H2B dimer (ceH2A.Z-H2B). Our structural and biochemical data reveals the acidic concave surface is relevant to tetramerization, and uncovers how a ceNAP1 homodimer uses its concave surface to asymmetrically recognize a ceH2A-H2B or ceH2A.Z-H2B heterodimer. Intriguingly, an "acidic strip" within the concave surface of ceNAP1 is crucial for binding histones, including H2A-H2B, H3-H4, and histone variants. Thus, our results provide insight into the molecular mechanisms of NAP1 histone chaperone activity.
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http://dx.doi.org/10.1016/j.str.2019.10.002DOI Listing
December 2019

Comparison of the participation rate between CT colonography and colonoscopy in screening population: a systematic review and meta-analysis of randomized controlled trials.

Br J Radiol 2020 Jan 1;93(1105):20190240. Epub 2019 Nov 1.

Department of Gastroenterology, The First Hospital of Jilin University, ChangChun, China.

Objective: To compare the participation rate between CT colonography (CTC) and colonoscopy in screening population in randomized controlled trials (RCTs).

Methods: A search was performed using the PubMed, Web of Science, and Cochrane databases. RCTs that included screening populations and reported participation number were assessed. Cochrane risk of bias tool was used to assess the bias and quality. Risk ratio (RR) was used to present the results. The non-participation rate was analyzed to verify the results of participation rate.

Results: Five of 760 studies, with a total of 15,974 invitees, were included. The participation rate was higher at CTC (28.8%) than colonoscopy (20.8%), although the difference did not reach statistical significance (RR = 1.26; = 0.070; I = 90.3%). The non-participation rate at CTC was significantly lower than colonoscopy (RR = 0.92; = 0.012; I = 86.7%). Subgroup analysis suggested both the participation and non-participation rate were with significant difference between reduced/no cathartic preparation CTC and colonoscopy. Cumulative meta-analysis showed both the participation rate and non-participation rate exhibited a trend over time and sample size.

Conclusion: The participation rate was higher at CTC than colonoscopy, although the difference did not reach statistical significance. But the non-participation rate was with statistical difference. Screening population seemed more likely to participate the reduced/no cathartic preparation CTC. Statistical evidence was provided for more large RCTs are needed in the future.

Advances In Knowledge: The screening populations seem more likely to participate in the CTC, especially the reduced/no cathartic preparation CTC. The statistical evidence was provided for more large RCTs are needed in the future.
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http://dx.doi.org/10.1259/bjr.20190240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948079PMC
January 2020

TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells.

Nat Commun 2019 09 19;10(1):4273. Epub 2019 Sep 19.

Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230026, China.

Recognition of specific chromatin modifications by distinct structural domains within "reader" proteins plays a critical role in the maintenance of genomic stability. However, the specific mechanisms involved in this process remain unclear. Here we report that the PHD-Bromo tandem domain of tripartite motif-containing 66 (TRIM66) recognizes the unmodified H3R2-H3K4 and acetylated H3K56. The aberrant deletion of Trim66 results in severe DNA damage and genomic instability in embryonic stem cells (ESCs). Moreover, we find that the recognition of histone modification by TRIM66 is critical for DNA damage repair (DDR) in ESCs. TRIM66 recruits Sirt6 to deacetylate H3K56ac, negatively regulating the level of H3K56ac and facilitating the initiation of DDR. Importantly, Trim66-deficient blastocysts also exhibit higher levels of H3K56ac and DNA damage. Collectively, the present findings indicate the vital role of TRIM66 in DDR in ESCs, establishing the relationship between histone readers and maintenance of genomic stability.
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http://dx.doi.org/10.1038/s41467-019-12126-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753139PMC
September 2019

Structural insights into the recognition of γ-globin gene promoter by BCL11A.

Cell Res 2019 Nov 29;29(11):960-963. Epub 2019 Aug 29.

Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, 230026, Hefei, Anhui, China.

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http://dx.doi.org/10.1038/s41422-019-0221-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888818PMC
November 2019

NMR Fragment-Based Screening against Tandem RNA Recognition Motifs of TDP-43.

Int J Mol Sci 2019 Jun 30;20(13). Epub 2019 Jun 30.

Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.

The TDP-43 is originally a nuclear protein but translocates to the cytoplasm in the pathological condition. TDP-43, as an RNA-binding protein, consists of two RNA Recognition Motifs (RRM1 and RRM2). RRMs are known to involve both protein-nucleotide and protein-protein interactions and mediate the formation of stress granules. Thus, they assist the entire TDP-43 protein with participating in neurodegenerative and cancer diseases. Consequently, they are potential therapeutic targets. Protein-observed and ligand-observed nuclear magnetic resonance (NMR) spectroscopy were used to uncover the small molecule inhibitors against the tandem RRM of TDP-43. We identified three hits weakly binding the tandem RRMs using the ligand-observed NMR fragment-based screening. The binding topology of these hits is then depicted by chemical shift perturbations (CSP) of the N-labeled tandem RRM and RRM2, respectively, and modeled by the CSP-guided High Ambiguity Driven biomolecular DOCKing (HADDOCK). These hits mainly bind to the RRM2 domain, which suggests the druggability of the RRM2 domain of TDP-43. These hits also facilitate further studies regarding the hit-to-lead evolution against the TDP-43 RRM domain.
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http://dx.doi.org/10.3390/ijms20133230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651732PMC
June 2019