Publications by authors named "Yin Shen"

197 Publications

Muscarinic acetylcholine receptor M5 is involved in spermatogenesis through the modification of cell-cell junctions.

Reproduction 2021 May 1. Epub 2021 May 1.

Y Zhao, Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China.

Muscarinic acetylcholine receptor (mAChR) antagonists have been reported to decrease male fertility, however the roles of mAChRs in spermatogenesis and the underlying mechanisms are not understood yet. During spermatogenesis, extensive remodeling between Sertoli cells and/or germ cells interfaces takes place to accommodate the transport of developing germ cells across the blood-testis barrier (BTB) and adluminal compartment. The cell-cell junctions play vital role in the spermatogenesis process. This study used ICR male mice and spermatogonial cells (C18-4) and Sertoli cells (TM-4). shRNA of control or M5 gene was injected into 5-week-age ICR mice testes. Ten days post viral grafting, mice were deeply anesthetized with pentobarbital and the testes were collected. One testicle was fresh frozen for RNA-seq analysis or Western blotting (WB). The second testicle was fixed for immunofluorescence staining (IHF). C18-4 or TM-4 cells were treated with shRNA of control or M5 gene. Then the cells were collected for RNA-seq analysis, WB, or IHF. Knockdown of mAChR M5 disrupted mouse spermatogenesis and damaged the actin-based cytoskeleton and many types of junction proteins in both Sertoli cells and germ cells. M5 knockdown decreased Phldb2 expression in both germ cells and Sertoli cells which suggested that Phldb2 may be involved in cytoskeleton and cell-cell junction formation to regulate spermatogenesis. Our investigation has elucidated a novel role for mAChR M5 in the regulation of spermatogenesis through the interactions of Phldb2 and cell-cell junctions. M5 may be an attractive future therapeutic target in the treatment of male reproductive disorders.
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http://dx.doi.org/10.1530/REP-21-0079DOI Listing
May 2021

A high-resolution typical pollution source emission inventory and pollution source changes during the COVID-19 lockdown in a megacity, China.

Environ Sci Pollut Res Int 2021 Apr 16. Epub 2021 Apr 16.

China-UK Low Carbon College, Shanghai Jiao Tong University, Shanghai, 200240, China.

To control the spread of COVID-19, China has imposed national lockdown policies to restrict the movement of its population since the Chinese New Year of January 2020. In this study, we quantitatively analyzed the changes of pollution sources in Shanghai during the COVID-19 lockdown; a high-resolution emission inventory of typical pollution sources including stationary source, mobile source, and oil and gas storage and transportation source was established based on pollution source data from January to February 2020. The results show that the total emissions of sulfur dioxide (SO), nitrogen oxides (NO), particulate matter (PM), and volatile organic compounds (VOCs) were 9520.2, 37,978.6, 2796.7, and 7236.9 tons, respectively, during the study period. Affected by the COVID-19 lockdown, the mobile source experienced the largest decline. The car mileage and oil sales decreased by about 80% during the COVID-19 lockdown (P3) when compared with those during the pre-Spring Festival (P1). The number of aircraft activity decreased by approximately 50%. The impact of the COVID-19 epidemic on industries such as iron and steel and petrochemicals was less significant, while the greater impact was on coatings, chemicals, rubber, and plastic. The emissions of SO, NO, PM, and VOCs decreased by 11%, 39%, 37%, and 47%, respectively, during P3 when compared with those during P1. The results show that the measures to control the spread of the COVID-19 epidemic made a significant contribution to emission reductions. This study may provide a reference for other countries to assess the impact of the COVID-19 epidemic on emissions and help establish regulatory actions to improve air quality.
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http://dx.doi.org/10.1007/s11356-020-11858-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052207PMC
April 2021

Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia.

Nat Commun 2021 04 16;12(1):2282. Epub 2021 Apr 16.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.

Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer-promoter interactions.
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http://dx.doi.org/10.1038/s41467-021-22470-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052326PMC
April 2021

GABAergic retinal ganglion cells regulate innate defensive responses.

Neuroreport 2021 May;32(7):643-649

Eye Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei.

Gamma-aminobutyric acid (GABA) is regarded as the most important inhibitory neurotransmitter in the central nervous system, including the retina. However, the roles of GABA-immunolabeled retinal ganglion cells (RGCs) have not been explored. Here, we report the expression of GABAergic RGCs that project to many brain areas in mice, including the superior colliculus. Selective ablation of the superior colliculus-projecting GABAergic RGCs, leaving other GABAergic RGCs intact, reduces the looming stimulus-induced defensive response without affecting image-forming functions; it also significantly enhances glucose metabolism in the superior colliculus, as determined by [18F]-fluorodeoxyglucose PET (FDG PET). Our findings demonstrate that superior colliculus-projecting GABAergic RGCs control the visually active defensive response by regulating superior colliculus neurons.
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http://dx.doi.org/10.1097/WNR.0000000000001652DOI Listing
May 2021

SMIXnorm: Fast and Accurate RNA-Seq Data Normalization for Formalin-Fixed Paraffin-Embedded Samples.

Front Genet 2021 24;12:650795. Epub 2021 Mar 24.

Department of Population and Data Sciences, Quantitative Biomedical Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, United States.

RNA-sequencing (RNA-seq) provides a comprehensive quantification of transcriptomic activities in biological samples. Formalin-Fixed Paraffin-Embedded (FFPE) samples are collected as part of routine clinical procedure, and are the most widely available biological sample format in medical research and patient care. Normalization is an essential step in RNA-seq data analysis. A number of normalization methods, though developed for RNA-seq data from fresh frozen (FF) samples, can be used with FFPE samples as well. The only extant normalization method specifically designed for FFPE RNA-seq data, MIXnorm, which has been shown to outperform the normalization methods, but at the cost of a complex mixture model and a high computational burden. It is therefore important to adapt MIXnorm for simplicity and computational efficiency while maintaining superior performance. Furthermore, it is critical to develop an integrated tool that performs commonly used normalization methods for both FF and FFPE RNA-seq data. We developed a new normalization method for FFPE RNA-seq data, named SMIXnorm, based on a simplified two-component mixture model compared to MIXnorm to facilitate computation. The expression levels of expressed genes are modeled by normal distributions without truncation, and those of non-expressed genes are modeled by zero-inflated Poisson distributions. The maximum likelihood estimates of the model parameters are obtained by a nested Expectation-Maximization algorithm with a less complicated latent variable structure, and closed-form updates are available within each iteration. Real data applications and simulation studies show that SMIXnorm greatly reduces computing time compared to MIXnorm, without sacrificing the performance. More importantly, we developed a web-based tool, , that offers a simple workflow to compute normalized RNA-seq data for both FFPE and FF samples. It includes SMIXnorm and MIXnorm for FFPE RNA-seq data, together with five commonly used normalization methods for FF RNA-seq data. Users can easily upload a raw RNA-seq count matrix and select one of the seven normalization methods to produce a downloadable normalized expression matrix for any downstream analysis. The R package is available at https://github.com/S-YIN/RSEQNORM. The web-based tool, is available at http://lce.biohpc.swmed.edu/rseqnorm with no restriction to use or redistribute.
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http://dx.doi.org/10.3389/fgene.2021.650795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024626PMC
March 2021

Double-strand breaks induce short scale DNA replication and damage amplification in the fully-grown mouse oocytes.

Genetics 2021 Apr 1. Epub 2021 Apr 1.

Fertility Preservation Lab, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China.

Break-induced replication (BIR) is essential for the repair of DNA double-strand breaks (DSBs) with single ends. DSBs-induced microhomology-mediated BIR (mmBIR) and template-switching can increase the risk of complex genome rearrangement. In addition, DSBs can also induce the multi-invasion-mediated DSB amplification. The mmBIR-induced genomic rearrangement has been identified in cancer cells and patients with rare diseases. However, when and how mmBIR are initiated haven't been fully and deeply studied. Furthermore, it is not well understood about the conditions for initiation of multi-invasion-mediated DSB amplification. In the G2 phase oocyte of mouse, we identified a type of short scale BIR (ssBIR) using the DNA replication indicator 5-ethynyl-2´-deoxyuridine (EdU). These ssBIRs could only be induced in the fully-grown oocytes but not the growing oocytes. If the DSB oocytes were treated with Rad51 or Chek1/2 inhibitors, both EdU signals and DSB marker γH2A.X foci would decrease. In addition, the DNA polymerase inhibitor Aphidicolin could inhibit the ssBIR and another inhibitor ddATP could reduce the number of γH2A.X foci in the DSB oocytes. In conclusion, our results showed that DNA DSBs in the fully-grown oocytes can initiate ssBIR and be amplified by Rad51 or DNA replication.
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http://dx.doi.org/10.1093/genetics/iyab054DOI Listing
April 2021

Assessment of spontaneous brain activity patterns in patients with iridocyclitis: a resting-state study.

Neuroreport 2021 May;32(7):612-620

Eye Center, Renmin Hospital of Wuhan University, Wuhan, Hubei.

Several studies demonstrated that patients with iridocyclitis were associated with vision loss and cognitive decline, whereas alterations in spontaneous brain activity occur in iridocyclitis patients remains unknown. The study aimed to explore spontaneous brain activity changes in iridocyclitis patients. Twenty-six patients with iridocyclitis and 26 healthy controls were finally included in our study. Resting-state MRI (rs-MRI) scan was conducted on both groups and the whole brain amplitude of low-frequency fluctuations (ALFFs) value was collected to assess differences in spontaneous brain activity. A receiver operating characteristic (ROC) curve was analyzed to distinguish between the fMRI data of patients with iridocyclitis and healthy controls. Patients with iridocyclitis showed significantly lower ALFF values in the right inferior parietal lobule, right calcarine, right superior temporal gyrus and right precentral gyrus compared to healthy controls and significantly higher ALFF values in the left superior frontal gyrus (P < 0.01, false discovery rate correction). The ROC curve analysis of different brain areas showed that the accuracies of ALFF value specificity between the iridocyclitis and healthy controls of the area under the curve were over 0.8. Our study highlighted an altered spontaneous activity in multiple brain regions, including the visual cortex, default-mode network, auditory area and sensorimotor areas in iridocyclitis. This may provide valuable information about underlying pathogenic mechanisms of iridocyclitis. These findings also indicate that rs-fMRI serves as a potential tool in the disease detection and evaluation of neurologic impairment in iridocyclitis.
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http://dx.doi.org/10.1097/WNR.0000000000001631DOI Listing
May 2021

The C. elegans homolog of human panic-disorder risk gene TMEM132D orchestrates neuronal morphogenesis through the WAVE-regulatory complex.

Mol Brain 2021 03 16;14(1):54. Epub 2021 Mar 16.

Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, 94158, USA.

TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of select WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.
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http://dx.doi.org/10.1186/s13041-021-00767-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962252PMC
March 2021

CharPlant: A De Novo Open Chromatin Region Prediction Tool for Plant Genomes.

Genomics Proteomics Bioinformatics 2021 Mar 1. Epub 2021 Mar 1.

Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. Electronic address:

Chromatin accessibility is a highly informative structural feature for understanding gene transcription regulation because it indicates the degree to which nuclear macromolecules such as proteins and RNAs can access chromosomal DNA. Studies show that chromatin accessibility is highly dynamic during stress response, stimulus response, and developmental transition. Moreover, physical access to chromosomal DNA in eukaryotes is highly cell-specific. Therefore, current technologies such as DNase-seq, ATAC-seq, and FAIRE-seq reveal only a portion of the open chromatin regions (OCRs) present in a given species. Thus, the genome-wide distribution of OCRs remains unknown. In this study, we developed a bioinformatics tool called CharPlant for the de novo prediction of OCRs in plant genomes. To develop this tool, we constructed a three-layer convolutional neural network (CNN) and subsequently trained the CNN using DNase-seq and ATAC-seq datasets of four plant species. The model simultaneously learns the sequence motifs and regulatory logics, which are jointly used to determine DNA accessibility. All of these steps are integrated into CharPlant, which can be run using a simple command line. The results of data analysis using CharPlant in this study demonstrate its prediction power and computational efficiency. To our knowledge, CharPlant is the first de novo prediction tool that can identify potential OCRs in the whole genome. The source code of CharPlant and supporting files are freely available from https://github.com/Yin-Shen/CharPlant.
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http://dx.doi.org/10.1016/j.gpb.2020.06.021DOI Listing
March 2021

Abnormal intrinsic functional network hubs in diabetic retinopathy patients.

Neuroreport 2021 Apr;32(6):498-506

Eye Center, Renmin Hospital of Wuhan University, Wuhan, Hubei.

Background: However, whether the whole-brain functional network hub changes occur in diabetic retinopathy patients remains unknown.

Purpose: The purpose of the study was to investigate the function network centrality and connectivity changes in diabetic retinopathy patients using the voxel-wise degree centrality method.

Materials And Methods: Thirty-four diabetic retinopathy patients (18 male and 16 female) and 38 healthy controls (18 male and 20 female) closely matched in age, sex, and education were enrolled in the study. Graph theory-based network analysis was performed to investigate the degree centrality between two groups.

Results: Compared with healthy controls, diabetic retinopathy patients had significantly higher degree centrality values in the pons and bilateral caudate and had significantly lower degree centrality values in the left lingual and right lingual, and right angular/middle occipital gyrus (MOG). Moreover, diabetic retinopathy patients exhibited increased functional connectivity between the bilateral lingual and right cerebellum lobe and right fusiform/bilateral caudate and increased functional connectivity between the right angular/MOG and bilateral anterior cingulum and right cuneus/bilateral precuneus and increased functional connectivity between the bilateral caudate and right lingual and right superior occipital gyrus. In contrast, diabetic retinopathy patients showed decreased functional connectivity between bilateral lingual and left lingual and right lingual and left superior occipital gyrus and decreased functional connectivity between the angular/MOG and right inferior occipital gyrus/right fusiform and left MOG/inferior occipital gyrus and decreased functional connectivity between the bilateral caudate and bilateral cerebellum crus1.

Conclusion: Our results highlight that reorganization of the hierarchy of the cortical connectivity network related to visual network.
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http://dx.doi.org/10.1097/WNR.0000000000001620DOI Listing
April 2021

Dynamic Changes of Amplitude of Low-Frequency Fluctuations in Patients With Diabetic Retinopathy.

Front Neurol 2021 11;12:611702. Epub 2021 Feb 11.

Eye Center, Renmin Hospital of Wuhan University, Wuhan, China.

Growing evidence demonstrate that diabetic retinopathy (DR) patients have a high risk of cognitive decline and exhibit abnormal brain activity. However, neuroimaging studies thus far have focused on static cerebral activity changes in DR patients. The characteristics of dynamic cerebral activity in patients with DR are poorly understood. The purpose of the study was to investigate the dynamic cerebral activity changes in patients with DR using the dynamic amplitude of low-frequency fluctuation (dALFF) method. Thirty-four DR patients (18 men and 16 women) and 38 healthy controls (HCs) (18 males and 20 females) closely matched in age, sex, and education were enrolled in this study. The dALFF method was used to investigate dynamic intrinsic brain activity differences between the DR and HC groups. Compared with HCs, DR patients exhibited increased dALFF variability in the right brainstem, left cerebellum_8, left cerebellum_9, and left parahippocampal gyrus. In contrast, DR patients exhibited decreased dALFF variability in the left middle occipital gyrus and right middle occipital gyrus. Our study highlighted that DR patients showed abnormal variability of dALFF in the visual cortices, cerebellum, and parahippocampal gyrus. These findings suggest impaired visual and motor and memory function in DR individuals. Thus, abnormal dynamic spontaneous brain activity might be involved in the pathophysiology of DR.
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http://dx.doi.org/10.3389/fneur.2021.611702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905082PMC
February 2021

Disrupted Neural Activity in Individuals With Iridocyclitis Using Regional Homogeneity: A Resting-State Functional Magnetic Resonance Imaging Study.

Front Neurol 2021 12;12:609929. Epub 2021 Feb 12.

Eye Center, Renmin Hospital of Wuhan University, Wuhan, China.

This study used the regional homogeneity (ReHo) technique to explore whether spontaneous brain activity is altered in patients with iridocyclitis. Twenty-six patients with iridocyclitis (14 men and 12 women) and 26 healthy volunteers (15 men and 11 women) matched for sex and age were enrolled in this study. The ReHo technique was used to comprehensively assess changes in whole-brain synchronous neuronal activity. The diagnostic ability of the ReHo method was evaluated by means of receive operating characteristic (ROC) curve analysis. Moreover, associations of average ReHo values in different brain areas and clinical characteristics were analyzed using correlation analysis. Compared with healthy volunteers, reduced ReHo values were observed in patients with iridocyclitis in the following brain regions: the right inferior occipital gyrus, bilateral calcarine, right middle temporal gyrus, right postcentral gyrus, left superior occipital gyrus, and left precuneus. In contrast, ReHo values were significantly enhanced in the right cerebellum, left putamen, left supplementary motor area, and left inferior frontal gyrus in patients with iridocyclitis, compared with healthy volunteers (false discovery rate correction, < 0.05). Patients with iridocyclitis exhibited disturbed synchronous neural activities in specific brain areas, including the visual, motor, and somatosensory regions, as well as the default mode network. These findings offer a novel image-guided research strategy that might aid in exploration of neuropathological or compensatory mechanisms in patients with iridocyclitis.
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http://dx.doi.org/10.3389/fneur.2021.609929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907498PMC
February 2021

Paraquat Reduces the Female Fertility by Impairing the Oocyte Maturation in Mice.

Front Cell Dev Biol 2020 2;8:631104. Epub 2021 Feb 2.

College of Life Sciences, Institute of Reproductive Science, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, China.

Paraquat (PQ) is a widely used non-selective and oxidizing herbicide in farmland, orchards, flower nursery, and grassland. Overuse of PQ will accumulate in the body and affect the reproduction in mammals. In this study, we found that PQ could reduce the female fertility by oral administration for 21 days in mice. PQ exposure could impair the nuclear maturation by perturbing the spindle assembly and kinetochore-microtubule attachment to cause the misaligned chromosomes during meiosis. In the meantime, PQ exposure disturbed the mitochondrial distribution and enhanced the level of reactive oxygen species and early apoptosis, which thereby deteriorated the early embryo development. Also, PQ administration could cause some changes in epigenetic modifications such as the level of H3K9me2 and H3K27me3. Therefore, PQ administration reduces the female fertility by impairing the nuclear and cytoplasmic maturation of oocytes in mice.
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http://dx.doi.org/10.3389/fcell.2020.631104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901924PMC
February 2021

CM082, a novel VEGF receptor tyrosine kinase inhibitor, can inhibit angiogenesis in vitro and in vivo.

Microvasc Res 2021 Feb 19;136:104146. Epub 2021 Feb 19.

Eye Center, Renmin Hospital of Wuhan University, No. 99 ZhangZhiDong Road, Wuhan 430060, Hubei, China. Electronic address:

The goal of this study was to evaluate the effects of CM082, a novel vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor, on human umbilical vein endothelial cells (HUVECs), and oxygen-induced retinopathy (OIR) mice. HUVECs were stimulated with rHuVEGF165 and then treated with CM082 to assess the antiangiogenic effects of CM082; subsequently, proliferation, wound-healing migration, Transwell invasion, tube formation assays, and Western blotting were performed in vitro. Retinal neovascularization tufts, avascular area, and TUNEL assays were estimated for OIR mice after intraperitoneal injection with CM082. CM082 significantly inhibited proliferation, migration, invasion, and tube formation induced by stimulation of HUVECs with rHuVEGF165; this inhibitory effect was mediated by blocking VEGFR2 activation. CM082 significantly inhibited retinal neovascularization and avascular area and did not increase apoptosis in the retina of OIR mice. The findings demonstrated that CM082 exhibits highly antiangiogenic effects in HUVECs and OIR mice. Thus, it may serve as an alternative treatment for neovascular eye disease in the future.
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http://dx.doi.org/10.1016/j.mvr.2021.104146DOI Listing
February 2021

COVID-2019 Associated with Acquired Monocular Blindness.

Curr Eye Res 2021 Feb 3:1-4. Epub 2021 Feb 3.

Eye Center, Wuhan University Renmin Hospital, Wuhan University, Wuhan, China.

: We documented an older female with Coronavirus(CoV) Disease 2019 (COVID-19) and concomitant acquired monocular blindness. We examined this phenomenon in order to understand COVID-19 better.: We observed an older female with COVID-19 and concomitant acquired monocular blindness. The following indicators were monitored during the course of the disease: ocular examinations, flash visual evoked potential examination, a blood test for COVID-19 IgM antibodies, as well as nasopharyngeal swab and tear sample tests for COVID-19 nucleic acid.: The patient's visual acuity for the left eye was NLP and the intraocular pressure was 51 mmHg. Keratic precipitates similar to mutton-fat were spread over the corneal endothelium of the left eye. The funduscopic examination of the patient's left eye revealed severe retinal arterial ischemia, and the color of the retina was off-white. Compared to the right eye, the flash visual evoked potential examination revealed a moderate decrease in P2 wave amplitude for the left eye. A blood test was positive for COVID-19 IgM antibodies, and a nasopharyngeal swab test taken for COVID-19 nucleic acid was positive on May 4, 2020. A sample of the patient's tears was taken, and the nucleic acid test for COVID-19 was still positive two weeks later.: Our study was the first to find that acute viral retinitis could occur in patients with COVID-19 and severe blindness could be associated with SARS-CoV-2 infection. Therefore, physicians should consider the possibility of coronavirus infection in patients with an abnormal fundus or suddenly vision loss.
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http://dx.doi.org/10.1080/02713683.2021.1874027DOI Listing
February 2021

Rescue of male fertility following faecal microbiota transplantation from alginate oligosaccharide-dosed mice.

Gut 2020 Dec 22. Epub 2020 Dec 22.

State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Haidian District, China

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http://dx.doi.org/10.1136/gutjnl-2020-323593DOI Listing
December 2020

Sox2 knockdown in the neonatal retina causes cell fate to switch from amacrine to bipolar.

Brain Res 2021 Feb 7;1752:147265. Epub 2021 Jan 7.

Eye Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, Hubei, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, Hubei, China. Electronic address:

Transcription factor Sox2 is widely recognized for its critical roles in the nervous system, including the neural retina. Here, we aimed to reveal the function of Sox2 in the process of mouse postnatal development. After the suppression of Sox2 at P0, there was an increase number in bipolar cells but a decrease in amacrine cells. Inhibited Sox2 expression also led to decreased visual function. Furthermore, we found a distinctive type of retinal cells expressing the characteristic proteins of both bipolar cells and amacrine cells at P6, which may be an intermediate state in which amacrine cells were transforming into bipolar cells. Transcription factors associated with the development of bipolar cells and amacrine cells also support those changes. Our work indicated that inhibition of Sox2 could change cell fate by affecting transcription factors in the development of bipolar cells and amacrine cells, may provide new directions for the study and treatment of retinal genetic diseases and retinal dysplasia.
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http://dx.doi.org/10.1016/j.brainres.2020.147265DOI Listing
February 2021

Derivation and validation of a prognostic model for predicting in-hospital mortality in patients admitted with COVID-19 in Wuhan, China: the PLANS (platelet lymphocyte age neutrophil sex) model.

BMC Infect Dis 2020 Dec 17;20(1):959. Epub 2020 Dec 17.

Department of Biostatistics, School of Public Health, and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.

Background: Previous published prognostic models for COVID-19 patients have been suggested to be prone to bias due to unrepresentativeness of patient population, lack of external validation, inappropriate statistical analyses, or poor reporting. A high-quality and easy-to-use prognostic model to predict in-hospital mortality for COVID-19 patients could support physicians to make better clinical decisions.

Methods: Fine-Gray models were used to derive a prognostic model to predict in-hospital mortality (treating discharged alive from hospital as the competing event) in COVID-19 patients using two retrospective cohorts (n = 1008) in Wuhan, China from January 1 to February 10, 2020. The proposed model was internally evaluated by bootstrap approach and externally evaluated in an external cohort (n = 1031).

Results: The derivation cohort was a case-mix of mild-to-severe hospitalized COVID-19 patients (43.6% females, median age 55). The final model (PLANS), including five predictor variables of platelet count, lymphocyte count, age, neutrophil count, and sex, had an excellent predictive performance (optimism-adjusted C-index: 0.85, 95% CI: 0.83 to 0.87; averaged calibration slope: 0.95, 95% CI: 0.82 to 1.08). Internal validation showed little overfitting. External validation using an independent cohort (47.8% female, median age 63) demonstrated excellent predictive performance (C-index: 0.87, 95% CI: 0.85 to 0.89; calibration slope: 1.02, 95% CI: 0.92 to 1.12). The averaged predicted cumulative incidence curves were close to the observed cumulative incidence curves in patients with different risk profiles.

Conclusions: The PLANS model based on five routinely collected predictors would assist clinicians in better triaging patients and allocating healthcare resources to reduce COVID-19 fatality.
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http://dx.doi.org/10.1186/s12879-020-05688-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744735PMC
December 2020

Factors associated with acute cardiac injury and their effects on mortality in patients with COVID-19.

Sci Rep 2020 11 24;10(1):20452. Epub 2020 Nov 24.

Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

To determine the incidence of acute cardiac injury (ACI), the factors associated with ACI and the in-hospital mortality in patients with COVID-19, especially in severe patients. All consecutive in-patients with laboratory-confirmed COVID-19 from Tongji Hospital in Wuhan during February 1 and March 29, 2020 were included. The demographic, clinical characteristics, laboratory, radiological and treatment data were collected. Univariate and Firth logistic regression analyses were used to identify factors associated with ACI and in-hospital mortality, and Kaplan-Meier method was used to estimate cumulative in-hospital mortality. Among 1031 patients included, 215 (20.7%) had ACI and 501 (48.6%) were severe cases. Overall, 165 patients died; all were from the severe group, and 131 (79.39%) had ACI. ACI (OR = 2.34, P = 0.009), male gender (OR = 2.58, P = 0.001), oximeter oxygen saturation (OR = 0.90, P < 0.001), lactate dehydrogenase (OR = 3.26, P < 0.001), interleukin-6 (IL-6) (OR = 8.59, P < 0.001), high sensitivity C-reactive protein (hs-CRP) (OR = 3.29, P = 0.016), N-terminal pro brain natriuretic peptide (NT-proBNP) (OR = 2.94, P = 0.001) were independent risk factors for the in-hospital mortality in severe patients. The mortality was significantly increased among severe patients with elevated hs-CRP, IL-6, hs-cTnI, and/or NT-proBNP. Moreover, the mortality was significantly higher in patients with elevation of both hs-cTnI and NT proBNP than in those with elevation of either of them. ACI develops in a substantial proportion of patients with COVID-19, and is associated with the disease severity and in-hospital mortality. A combination of hs-cTnI and NT-proBNP is valuable in predicting the mortality.
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http://dx.doi.org/10.1038/s41598-020-77172-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686361PMC
November 2020

Prescribed Performance Quantized Tracking Control for a Class of Delayed Switched Nonlinear Systems With Actuator Hysteresis Using a Filter-Connected Switched Hysteretic Quantizer.

IEEE Trans Neural Netw Learn Syst 2020 Oct 19;PP. Epub 2020 Oct 19.

This article proposes a prescribed adaptive backstepping scheme with new filter-connected switched hysteretic quantizer (FCSHQ) for switched nonlinear systems with nonstrict-feedback structure and time-delay. The system model is subjected to unknown functions, unknown delays, and unknown Bouc-Wen hysteresis nonlinearity. The coexistence of quantized input and actuator hysteresis may deteriorate the shape of hysteresis loop and, consequently, fail to guarantee the stability. To deal with this issue, a new FCSHQ is introduced to smooth the input hysteresis. This adaptive filter also provides us a degree of freedom at choosing the desired communication rate. The repetitive differentiations of virtual control laws and existing a lot of learning parameters in the neural network (NN)-based controller may result in an algebraic loop problem and high computational time, especially in a nonstrict-feedback form. This challenge is eased by the key advantage of NNs' property where the upper bound of the weight vector is employed. Then, by an appropriate Lyapunov-Krasovskii functional, a common Lyapunov function is presented for all subsystems. It is shown that the proposed controller ensures the predefined output tracking accuracies and boundedness of the closed-loop signals under any arbitrary switching. Finally, the proposed control scheme is verified on a practical example where simulation results demonstrate the effectiveness of the proposed scheme.
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http://dx.doi.org/10.1109/TNNLS.2020.3027492DOI Listing
October 2020

Cell-type-specific 3D epigenomes in the developing human cortex.

Nature 2020 11 14;587(7835):644-649. Epub 2020 Oct 14.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.
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http://dx.doi.org/10.1038/s41586-020-2825-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704572PMC
November 2020

Altered Intrinsic Brain Activities in Patients with Diabetic Retinopathy Using Amplitude of Low-frequency Fluctuation: A Resting-state fMRI Study.

Diabetes Metab Syndr Obes 2020 13;13:2833-2842. Epub 2020 Aug 13.

Eye Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, People's Republic of China.

Objective: The current study aimed to apply the amplitude of low-frequency fluctuation (ALFF) method for investigating the spontaneous brain activity alterations and their relationships with clinical features in patients with diabetic retinopathy (DR).

Patients And Methods: In total, 35 patients with DR (18 males and 17 females) and 38 healthy control (HC) subjects (18 males and 20 females) were enrolled in this study. All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning, respectively. The ALFF method was used to assess the spontaneous brain activity, while the mean ALFF signal values of patients with DR and HCs were classified by the receiver operating characteristic (ROC) curve. Correlation analysis was performed to calculate the relationship between the observed mean ALFF values of the altered regions in patients with DR and their clinical features.

Results: Compared with the HCs, patients with DR had significantly lower ALFF values in the left and right middle occipital gyrus (MOG). In contrast, patients with DR showed higher ALFF values in the left cerebellum (CER), left inferior temporal gyrus (ITG) and left hippocampus (Hipp). However, no relationship was observed between the mean ALFF signal values of the altered regions and clinical manifestations in the patients with DR.

Conclusion: We mainly found that patients with DR showed abnormal intrinsic brain activities in the left and right MOG, left CER, left ITG and left Hipp, which might provide useful information for explaining neural mechanisms in patients with DR.
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http://dx.doi.org/10.2147/DMSO.S259476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434521PMC
August 2020

Study on terahertz spectrum analysis and recognition modeling of common agricultural diseases.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Dec 11;243:118820. Epub 2020 Aug 11.

Beijing Research Center of Intelligent Equipment for Agriculture, Beijing, PR China; Key Laboratory of Quantitative Remote Sensing in Agriculture, Ministry of Agriculture, PR China.

Diseases are critical factors that affect the yield and quality of crops. Therefore, it is of great research value to develop rapid and quantitative methods for identification of common agricultural diseases. This exploratory study involved data analysis of common fungal pathogens using identification modeling based on terahertz spectrum technology. The selected pathogens were Physalospora piricola, Erysiphe cichoracearum, and Botrytis cinerea, which are common fungal pathogens that cause apple ring rot, cucumber powdery mildew, and grape gray mold blight, respectively. Taking polyethylene as the control, the terahertz time-domain spectra, and frequency-domain spectra of samples of the three pathogens were both measured. The absorption and refraction characteristics of these samples in the range of 0.1-2.0 THz were calculated and analyzed, and samples were then divided using the KS algorithm. Terahertz spectrum-image data blocks of the pathogen samples were preprocessed, and the dimensions of data were reduced using non-local mean filtering and the SPA algorithm, respectively. K-nearest neighbors (KNN), support vector machine (SVM), and BP neural network (BPNN), and other algorithms were used for analysis of terahertz images at characteristic frequencies, and for investigating the identification model. The model was quantitatively evaluated, and its imaging visualization was studied. The results suggest that there are significant differences among P. piricola, E. cichoracearum, and B. cinerea in absorption and refraction in the terahertz band. SVM modeling identification results of the three pathogens at the frequency of 1.376 THz were satisfactory, with an R of 0.9649, RMSEP of 0.0273, and a high (93.8212%) comprehensive evaluation index F1-score, and a clearly identifiable visualization effect. This study demonstrated the potential of terahertz spectroscopy to be used for identification of common crop pathogens and has provided technical references for the rapid diagnosis and early warning of agricultural diseases.
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http://dx.doi.org/10.1016/j.saa.2020.118820DOI Listing
December 2020

A cell-permeable peptide inhibitor of p55PIK signaling alleviates ocular inflammation in mouse models of uveitis.

Exp Eye Res 2020 10 8;199:108180. Epub 2020 Aug 8.

Eye Center, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, Hubei, China. Electronic address:

Purpose: Previously we developed TAT-N24 as a synthetic cell-permeable peptide inhibitor of p55PIK signaling and demonstrated its anti-inflammatory effects. This study aimed to evaluate the potential of TAT-N24 as a new agent for the treatment of ocular inflammatory diseases.

Methods: The endotoxin-induced uveitis (EIU) model was established by intravitreal injection of lipopolysaccharide (LPS) in BALB/c mice and experimental autoimmune uveitis (EAU) model was established by subcutaneous injection of a peptide spanning amino acid residues 161-180 of interphotoreceptor retinoid binding protein (IRBP161-180) with complete Freund's adjuvant (CFA) in B10.RIII mice. TAT-N24 was topically administered in EIU model and intraperitoneally administered in EAU model. The severity levels of uveitis were assessed by clinical and histopathological scores. The mRNA levels of inflammatory cytokines in iris-ciliary body (ICB) and retina were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein levels of inflammatory factors were determined by ELISA or Western blotting.

Results: The results showed that TAT-N24 alleviated clinical signs, decreased inflammatory cell infiltration and the expression of inflammatory cytokines in both EIU and EAU models. Furthermore, protein levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in aqueous humor and mRNA and protein levels of NF-κB p65 in the ICB significantly decreased in EIU model. In EAU model, TAT-N24 application induced a significant decrease of IFN-gamma (IFN-γ) and interleukin-17 (IL-17) in the retina, which were secreted by Th1 and Th17 cells, respectively.

Conclusion: In conclusion, TAT-N24 suppressed intraocular inflammation in both EIU and EAU models, and the anti-inflammatory effects were mediated by suppressing the expression of inflammatory cytokines by PI3K/NF-κB signaling pathway. TAT-N24 could be potential candidate for the treatment of ocular inflammatory diseases.
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http://dx.doi.org/10.1016/j.exer.2020.108180DOI Listing
October 2020

Automated identification of retinopathy of prematurity by image-based deep learning.

Eye Vis (Lond) 2020 1;7:40. Epub 2020 Aug 1.

Eye Center, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei China.

Background: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide but can be a treatable retinal disease with appropriate and timely diagnosis. This study was performed to develop a robust intelligent system based on deep learning to automatically classify the severity of ROP from fundus images and detect the stage of ROP and presence of plus disease to enable automated diagnosis and further treatment.

Methods: A total of 36,231 fundus images were labeled by 13 licensed retinal experts. A 101-layer convolutional neural network (ResNet) and a faster region-based convolutional neural network (Faster-RCNN) were trained for image classification and identification. We applied a 10-fold cross-validation method to train and optimize our algorithms. The accuracy, sensitivity, and specificity were assessed in a four-degree classification task to evaluate the performance of the intelligent system. The performance of the system was compared with results obtained by two retinal experts. Moreover, the system was designed to detect the stage of ROP and presence of plus disease as well as to highlight lesion regions based on an object detection network using Faster-RCNN.

Results: The system achieved an accuracy of 0.903 for the ROP severity classification. Specifically, the accuracies in discriminating normal, mild, semi-urgent, and urgent were 0.883, 0.900, 0.957, and 0.870, respectively; the corresponding accuracies of the two experts were 0.902 and 0.898. Furthermore, our model achieved an accuracy of 0.957 for detecting the stage of ROP and 0.896 for detecting plus disease; the accuracies in discriminating stage I to stage V were 0.876, 0.942, 0.968, 0.998 and 0.999, respectively.

Conclusions: Our system was able to detect ROP and differentiate four-level classification fundus images with high accuracy and specificity. The performance of the system was comparable to or better than that of human experts, demonstrating that this system could be used to support clinical decisions.
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http://dx.doi.org/10.1186/s40662-020-00206-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395360PMC
August 2020

Protocol development for real-time ship fuel sulfur content determination using drone based plume sniffing microsensor system.

Sci Total Environ 2020 Nov 16;744:140885. Epub 2020 Jul 16.

Division of Environment and Sustainability, The Hong Kong University of Science and Technology, Hong Kong, China; Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality, China. Electronic address:

Pollutants from navigation sector are key contributors to emission inventories of most coastal cities with heavy port activities. The use of high fuel sulfur content (FSC) bunker oil by ocean going vessels (OGVs) has been identified as a major source of sulfur dioxide (SO). Government authorities all over the world, including Hong Kong government, have implemented air pollution control regulations to cap FSC of fuel used by OGVs to 0.5%, from the existing 3.5%, to reduce SO emissions. However, the lack of efficient screening tools to identify non-compliant OGVs has prevented effective enforcement. This study developed and evaluated an unmanned aerial vehicle (UAV)-borne lightweight (750 g) microsensor system (MSS), which is capable of measuring ship plume SO, NO, NO, CO, CO, and particulate matter in real-time. Extensive experiments were conducted on the sensor system to evaluate its performance during laboratory and field operations. The effects of cross-sensitivity and meteorological conditions were studied and incorporated to account for the measurement conditions in dispersed ship plumes. The SO to CO concentration ratio-based FSC expression was formulated as per the 2016 European Union Directive and Regulations. Furthermore, the impact of plume dilution on the accuracy of FSC measurement was investigated at different stages using the MSS, with and without the UAV in both simulated conditions and real-world scenarios, maintaining a safe distance from the OGV exhaust stacks. The study demonstrates the robustness of using UAV-borne sensor system for ship emission sniffing and FSC determination. The results will assist in development of a technological framework for effective enforcement of ship emission control regulations.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140885DOI Listing
November 2020

Expanded encyclopaedias of DNA elements in the human and mouse genomes.

Nature 2020 07 29;583(7818):699-710. Epub 2020 Jul 29.

Department of Biological Science, Florida State University, Tallahassee, FL, USA.

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE and Roadmap Epigenomics data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.
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http://dx.doi.org/10.1038/s41586-020-2493-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410828PMC
July 2020

An atlas of dynamic chromatin landscapes in mouse fetal development.

Nature 2020 07 29;583(7818):744-751. Epub 2020 Jul 29.

Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA, USA.

The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP-seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC-seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date.
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http://dx.doi.org/10.1038/s41586-020-2093-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398618PMC
July 2020