Biology subjects

Bai, Y.

Publications and source records attributed to Bai, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2021

Characterization of a Novel Type Homoserine Dehydrogenase Only with High Oxidation Activity from Arthrobacter nicotinovorans

Homoserine dehydrogenase (HSD) is a key enzyme in the synthesis pathway of the aspartate family of amino acids. HSD can catalyze the reversible reaction of L-aspartate-{beta}-semialdehyde (L-ASA) to L-homoserine (L-Hse). In direct contrast, growth characteristic studies of some bacterial such as Arthrobacter nicotinovorans showed that the bacterium could grow well in medium with L-homoserine as sole carbon, nitrogen and energy source, but the genes responsible for the degradation of L-Hse remain unknown. Based on the function and sequence analysis of HSD, one putative homoserine dehydrogenase from A.nicotinovorans was named AnHSD, which was different from those HSDs that from the aspartic acid metabolic pathway, might be responsible for the degradation of L-Hse. Surprisingly, the analysis showed that the purified AnHSD exhibited specific L-Hse oxidation activity without reducing activity. At pH 10.0 and 40 {degrees}C, The Km and Kcat of AnHSD was 6.30 {+/-} 1.03 mM and 462.71 s-1, respectively. AnHSD was partiality for NAD+ cofactor, as well as insensitive to feedback inhibition of downstream amino acids of aspartic acid family. The physiological role of AnHSD in A.nicotinovorans is discussed. These findings provide a novel insight for a better understanding of an alternative genetic pathway for L-Hse catabolism which was dominated by the novel HSD. ImportanceL-homoserine is an important building block for the synthesis of L-threonine, L-methionine, L-lysine which from aspartic acid family amino acids. However, some bacteria can make use of L-homoserine as a sole carbon and nitrogen source. Although the microbial degradation of L-homoserine has been studied several times, the genes involved and the molecular mechanisms remain unclear. In this study, we show that AnHSD responsible for the catabolism of L-homoserine in strain Arthrobacter nicotinovorans, as a special homoserine dehydrogenase with high diversity exists in Arthrobacter, Microbacterium, Rhizobium. We report for the first time that this novel homoserine dehydrogenase is now proposed to play a crucial role in that L-homoserine can use as a sole carbon and nitrogen source. This study is aimed at elucidating the enzymatic properties and function features of homoserine dehydrogenase from Arthrobacter nicotinovorans. These findings provide new insight into the catabolism of L-homoserine in bacteria.

microbiology↗

bioRxiv2021

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib isdriven by off-target Ferrochelatase inhibition

A multitude of disease and therapy related factors drive the frequent development of renal disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause renal dysfunction through on and off-target mechanisms. Interestingly, among the small-molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury (AKI). To investigate the underlying mechanisms, here, we have developed cell culture and mouse models of vemurafenib nephrotoxicity. Our studies show that at clinically relevant concentrations vemurafenib induces cell-death in transformed and primary murine and human renal tubular epithelial cells (RTEC). In mice, two weeks of daily vemurafenib treatment causes moderate AKI with histopathological characteristics of RTEC injury. Importantly, RTEC-specific BRAF gene deletion did not influence renal function under normal conditions or alter the severity of vemurafenib-associated renal impairment. Instead, we found that inhibition of ferrochelatase (FECH), an enzyme involved in heme biosynthesis contributes to vemurafenib nephrotoxicity. FECH overexpression protected RTECs and conversely FECH knockdown increased the sensitivity to vemurafenib nephrotoxicity. Collectively, these studies suggest that vemurafenib-associated RTEC dysfunction and nephrotoxicity is BRAF-independent and caused in part by off-target FECH inhibition. Translational StatementBRAF is the most frequently mutated protein kinase and a critical oncogenic driver in human cancers. In melanoma and other cancers with BRAF activating mutations, BRAF targeted small-molecule therapeutics such as vemurafenib, and dabrafenib have shown remarkable clinical benefits. However, recent clinical studies have shown that a significant number of patients that receive vemurafenib develop AKI through mechanisms that remain unknown. The present study describes the development of novel experimental models of vemurafenib nephrotoxicity and reveals the underlying off-target mechanisms that contribute to renal injury.

pharmacology and toxicology↗

bioRxiv2021

Reference-based error correction of amplicon sequencing data from synthetic communities

SummarySynthetic microbial communities (SynComs) constitute an emerging and powerful tool in biological, biomedical, and biotechnological research. Despite recent advances in algorithms for the analysis of culture-independent amplicon sequencing data from microbial communities, there is a lack of tools specifically designed for analysing SynCom data, where reference sequences for each strain are available. Here we present Rbec, a tool designed for the analysis of SynCom data that accurately corrects PCR and sequencing errors in amplicon sequences and identifies intra-strain polymorphic variation. Extensive evaluation using mock bacterial and fungal communities show that our tool outperforms current methods for samples of varying complexity, diversity, and sequencing depth. Furthermore, Rbec also allows accurate detection of contaminants in SynCom experiments. Availability and implementationRbec is freely available as an open-source multi-platform R package. Release versions can be obtained via Bioconductor. The developer version is maintained and can be downloaded at: https://github.com/PengfanZhang/Rbec. Contactgarridoo@mpipz.mpg.de

bioinformatics↗

bioRxiv2020

Real-time monitoring epidemic trends and key mutations in SARS-CoV-2 evolution by an automated tool

With the global epidemic of SARS-CoV-2, it is important to monitor the variation, haplotype subgroup epidemic trends and key mutations of SARS-CoV-2 over time effectively, which is of great significance to the development of new vaccines, the update of therapeutic drugs, and the improvement of detection reagents. The AutoVEM tool developed in the present study could complete all mutations detections, haplotypes classification, haplotype subgroup epidemic trends and key mutations analysis for 131,576 SARS-CoV-2 genome sequences in 18 hours on a 1 core CPU and 2G internal storage computer. Through haplotype subgroup epidemic trends analysis of 131,576 genome sequences, the great significance of the previous 4 specific sites (C241T, C3037T, C14408T and A23403G) was further revealed, and 6 new mutation sites of highly linked (T445C, C6286T, C22227T, G25563T, C26801G and G29645T) were discovered for the first time that might be related to the infectivity, pathogenicity or host adaptability of SARS-CoV-2. In brief, we proposed an integrative method and developed an efficient automated tool to monitor haplotype subgroup epidemic trends and screen out the key mutations in the evolution of SARS-CoV-2 over time for the first time, and all data could be updated quickly to track the prevalence of previous key mutations and new key mutations because of high efficiency of the tool. In addition, the idea of combinatorial analysis in the present study can also provide a reference for the mutation monitoring of other viruses.

genomics↗

bioRxiv2020

AdRoit: an accurate and robust method to infer complex transcriptome composition

Bulk RNA sequencing technology provides the opportunity to understand biology at the whole transcriptome level without the prohibitive cost of single cell profiling. Advances in spatial transcriptomics enable to dissect tissue organization and function by genome-wide gene expressions. However, the readout of both technologies is the overall gene expression across potentially many cell types without directly providing the information of cell type constitution. Although several in-silico approaches have been proposed to deconvolute RNA-Seq data composed of multiple cell types, many suffer a deterioration of performance in complex tissues. Here we present AdRoit, an accurate and robust method infer the cell composition from transcriptome data comprised of multiple cell types. AdRoit uses gene expression profile obtained from single cell RNA sequencing as a reference. It employs an adaptive learning approach to correct the sequencing technique difference between the single cell data and the bulk or spatial transcriptome data, enabling cross-platform readout comparability. Our systematic benchmarking and applications, which include deconvoluting complex mixtures that encompass 30 cell types, demonstrate its superior sensitivity and specificity compared to other existing methods as well as its utilities. In addition, AdRoit is computationally efficient and runs orders of magnitude faster than many existing methods.

bioinformatics↗

bioRxiv2020

Establishment of Multi-stage Models of Drug Taking and Seeking in Mice

A genetically tractable animal model would provide a needed strategy to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling cocaine and opioid addiction in animals, but technical limitations have precluded the widespread use of IVSA in mice. Here, we describe the first IVSA paradigms for mice that capture the multi-stage nature of the disease and permit predictive modeling. Mice with long-standing indwelling jugular catheters engaged in cocaine or opioid-associated lever responding that was fixed ratio- and dose-dependent, extinguished by the withholding of drug, and reinstated by the presentation of paired cues. Machine learning revealed that vulnerability to drug seeking and relapse were predicted by a mouses a priori response to novelty, sensitivity to drug-induced locomotion, and drug-taking behavior. Application of this behavioral and analysis approach to genetically-engineered mice will facilitate the identification of the neural circuits driving addiction susceptibility and relapse and focused therapeutic development.

neuroscience↗

bioRxiv2020

A cis-regulatory element promoting increased transcription at low temperature in cultured ectothermic Drosophila cells

Cells of many ectothermic species, including Drosophila melanogaster, maintain homeostatic function within a considerable temperature range. The cellular mechanisms enabling temperature acclimation are still poorly understood. At the transcriptional level, the heat shock response has been extensively analyzed. The opposite has received less attention. Here, using cultured Drosophila cells, we have identified genes with increased transcript levels at the lower end of the readily tolerated temperature range, as well as chromatin regions with increased DNA accessibility. Candidate cis-regulatory elements (CREs) for transcriptional upregulation at low temperature were selected and evaluated with a novel reporter assay for accurate assessment of their temperature-dependency. Robust transcriptional upregulation at low temperature could be demonstrated for a fragment from the pastrel gene, which expresses more transcript and protein at reduced temperatures. The CRE is controlled by the JAK/STAT signaling pathway and antagonizing activities of the transcription factors Pointed and Ets97D.

cell biology↗

bioRxiv2020

First high-quality reference genome of Amphicarpaea edgeworthii

Amphicarpaea edgeworthii, an annual twining herb, is a widely distributed species and an ideal model for studying complex flowering types and evolutionary mechanisms of species. Herein, we generated a high-quality assembly of A. edgeworthii by using a combination of PacBio, 10x Genomics libraries, and Hi-C mapping technologies. The final 11 chromosome-level scaffolds covered 90.61% of the estimated genome (343.78 Mb), which is the first chromosome-scale assembled genome of an amphicarpic plant. These data will be beneficial for the discovery of genes that control major agronomic traits, spur genetic improvement of and functional genetic studies in legumes, and supply comparative genetic resources for other amphicarpic plants.

genomics↗

bioRxiv2020

A three-dimensional Air-Liquid Interface Culture Model for the Study of Epstein-Barr virus Infection in the Nasopharynx

Epstein-Barr virus (EBV) infection is ubiquitous in humans and is associated with the cancer, nasopharyngeal carcinoma. EBV replicates in the differentiated layers of stratified keratinocytes but whether the other cell types of the airway epithelium are susceptible to EBV is unknown. Here, we demonstrate with primary nasopharyngeal cells grown at the air-liquid interface that the pseudostratified epithelium can be susceptible to EBV infection and we report that susceptible cell types with distinct EBV transcription profiles can be identified by single-cell RNA-sequencing. Although EBV infection in the nasopharynx has evaded detection in asymptomatic carriers, these findings demonstrate that EBV latent and lytic infection can occur in the cells of the nasopharyngeal epithelium.

microbiology↗

bioRxiv2020

Transcription factor-based gene therapy to treat glioblastoma through direct neuronal conversion

Glioblastoma (GBM) is the most prevalent and aggressive adult primary cancer in the central nervous system (CNS). Therapeutic approaches for glioblastoma are under intense investigation, such as the emerging immunotherapy, but so far only marginal progress has been made due to the heterogeneity and highly invasive nature of glioblastoma. Here, we propose an alternative approach to tackle GBM through reprogramming proliferative GBM cells into non-proliferative neurons. We report efficient neuronal conversion from human GBM cells by overexpressing single neural transcription factor Neurogenic differentiation 1 (NeuroD1), Neurogenin-2 (Neurog2) or Achaete-scute homolog 1 (Ascl1). Subtype characterization reveals that the majority of Neurog2- and NeuroD1-converted neurons are glutamatergic, while Ascl1 favors GABAergic neuron generation. The GBM cell-converted neurons not only express pan-neuronal markers, such as NeuN and MAP2, but also exhibit neuron-specific electrophysiological activities. We further conducted transcriptome analyses to investigate the underlying cell conversion mechanism. Our RNA-seq analyses discover that neuronal genes are activated among glioma cells after overexpression of neural transcription factors, and different signaling pathways are activated by different neural transcription factors. Importantly, the neuronal conversion of GBM cells is accompanied by significant inhibition of GBM cell proliferation in both in vitro and in vivo models. Therefore, these results suggest that GBM cells can be reprogrammed into different subtypes of neurons, leading to a potential alternative approach to treat brain tumor. SignificanceConverting dividing glioblastoma cells into non-dividing neurons may provide an innovative therapeutic approach to treat glioblastoma. HighlightsO_LIEfficient neuronal conversion of human glioblastoma cells achieved by overexpression of neural transcription factors C_LIO_LINeurog2- and NeuroD1-converted neurons are mostly glutamatergic, while Ascl1-converted neurons are mainly GABAergic C_LIO_LITranscriptome analyses reveal the activation of neuronal genes after overexpression of neural transcription factors in glioblastoma cells C_LIO_LIInhibition of cell proliferation during glioblastoma cell conversion both in vitro and in vivo C_LI

neuroscience↗

bioRxiv2020

Identifying genes and cell types with dynamic alternative polyadenylation in multi-cluster single-cell transcriptomics data

Alternative polyadenylation (APA) causes shortening or lengthening of the 3-untranslated region (3-UTR) of genes across multiple cell types. Bioinformatic tools have been developed to identify genes that are affected by APA (APA genes) in single-cell RNA-Seq (scRNA-Seq) data. However, they suffer from low power, and they cannot identify APA genes specific to each cell type (cell-type-specific APA) when multiple cell types are analyzed. To address these limitations, we developed scMAPA that systematically integrates two novel steps. First, scMAPA quantifies 3-UTR long and short isoforms without requiring assumptions on the read density shape of input data. Second, scMAPA estimates the significance of the APA genes for each cell type while controlling confounders. In the analyses on our novel simulation data and human peripheral blood mono cellular data, scMAPA showed enhanced power in identifying APA genes. Further, in mouse brain data, scMAPA identifies cell-type-specific APA genes, improving interpretability for the cell-type-specific function of APA. We further showed that this improved interpretability helps to understand a novel role of APA on the interaction between neurons and blood vessels, which is critical to maintaining the operational condition of brains. With high sensitivity and interpretability, scMAPA shed novel insights into the function of dynamic APA in complex tissues. Key PointsO_LIWe developed a bioinformatic tool, scMAPA, that identifies dynamic APA across multiple cell types and a novel simulation pipeline to assess performance of such tools in APA calling. C_LIO_LIIn simulation data of various scenarios from our novel simulation pipeline, scMAPA achieves sensitivity with a minimal loss of specificity. C_LIO_LIIn human peripheral blood monocellular data, scMAPA identifies APA genes accurately and robustly, finding unique associations of APA with hematological processes. C_LIO_LIscMAPA identifies APA genes specific to each cell type in mouse brain data while controlling confounders that sheds novel insights into the complex molecular processes. C_LI

bioinformatics↗

bioRxiv2020

SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in kidney epithelial cells

Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, as well as cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxic, cytotoxic, and inflammatory insults to renal tubular epithelial cells (RTECs) resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that Vgf nerve growth factor inducible gene upregulation is a common transcriptional stress response in RTECs to ischemia, cisplatin, and rhabdomyolysis-associated renal injury. The Vgf gene encodes a secretory peptide precursor protein that has critical neuro-endocrine functions; however, its role in the kidneys remains unknown. Our functional studies show that RTEC-specific Vgf gene ablation exacerbates ischemia, cisplatin, and rhabdomyolysis-associated AKI in vivo and cisplatin-induced RTEC cell death in vitro. Importantly, addback experiments showed that aggravation of cisplatin-induced renal injury caused by Vgf gene ablation is partly reversed by TLQP-21, a Vgf-derived peptide. Finally, in vitro and in vivo mechanistic studies showed that injury-induced Vgf upregulation in RTECs is driven by the transcriptional regulator Sox9. These findings reveal a crucial downstream target of the Sox9-directed transcriptional program and identify Vgf as a stress-responsive protective gene in kidney epithelial cells.AbbreviationsAKIAcute kidney injuryRTECrenal tubular epithelial cellsBUNblood urea nitrogenChIPchromatin immunoprecipitationSox9SRY-Box transcription factor 9.View Full Text

cell biology↗

bioRxiv2020

Individual cell-based modeling of tumor cell plasticity-induced immune escape after CAR-T therapy

Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially B cell acute lymphoblastic leukemia (B-ALL). The majority of patients achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CAR-19 T cells); however, many patients suffer relapse after therapy, and the underlying mechanism remains unclear. To better understand the mechanism of tumor relapse, we developed an individual cell based computational model for tumor cell plasticity and the heterogeneous responses to the CAR-T treatment. Model simulations reproduced the process of tumor relapse, and predicted that CAR-T stress-induced cell plasticity can lead to tumor relapse in B-ALL. Model predictions were verified by applying the second-generation CAR-T cells to mice injected with NALM-6-GL leukemic cells, in which 60% of the mice relapse within 3 months, and relapsed tumors retained CD19 expression but exhibited a subpopulation of cells with CD34 transcription. These findings lead to a mechanism of tumor replace by which CAR-T treatment induced tumor cells to transition to hematopoietic stem-like cells (HSLCs) and myeloid-like cells and hence escape of CAR-T targeting. The computational model framework was successfully developed to recapitulate the individual evolutionary dynamics, which could predict clinical survival outcomes in B-ALL patients after CAR-T therapy.

cancer biology↗

bioRxiv2020

Comparative genomics of Verticillium dahliae isolates reveals the in planta-secreted effector protein recognized in V2 tomato plants

Plant pathogens secrete effector molecules during host invasion to promote host colonization. However, some of these effectors become recognized by host receptors, encoded by resistance genes, to mount defense response and establish immunity. Recently, a novel resistance was identified in tomato, mediated by the single dominant V2 locus, to control strains of the soil-borne vascular wilt fungus Verticillium dahliae that belong to race 2. We performed comparative genomics between race 2 strains and resistance-breaking race 3 strains to identify the avirulence effector that activates V2 resistance, termed Av2. We identified 277 kb of race 2-specific sequence comprising only two genes that encode predicted secreted proteins, both of which are expressed by V. dahliae during tomato colonization. Subsequent functional analysis based on genetic complementation into race 3 isolates confirmed that one of the two candidates encodes the avirulence effector Av2 that is recognized in V2 tomato plants. The identification of Av2 will not only be helpful to select tomato cultivars that are resistant to race 2 strains of V. dahliae, as the corresponding V2 resistance gene has not yet been mapped, but also to monitor adaptations in the V. dahliae population to deployment of V2-containing tomato cultivars in agriculture.

plant biology↗

bioRxiv2020

A systematic dissection of human primary osteoblasts in vivo at single-cell resolution

Osteoblasts are multifunctional bone cells, which play essential roles in bone formation, angiogenesis regulation, as well as maintenance of hematopoiesis. Although both in vivo and in vitro studies on mice have identified several potential osteoblast subtypes based on their different transition stages or biological responses to external stimuli, the categorization of primary osteoblast subtypes in vivo in humans has not yet been achieved. Here, we used single-cell RNA sequencing (scRNA-seq) to perform a systematic cellular taxonomy dissection of freshly isolated human osteoblasts. Based on the gene expression patterns and cell lineage reconstruction, we identified three distinct cell clusters including preosteoblasts, mature osteoblasts, and an undetermined rare osteoblast subpopulation. This novel subtype was mainly characterized by the nuclear receptor subfamily 4 group A member 1 and 2 (NR4A1 and NR4A2), and its existence was confirmed by immunofluorescence staining. Trajectory inference analysis suggested that the undetermined cluster, together with the preosteoblasts, are involved in the regulation of osteoblastogenesis and also give rise to mature osteoblasts. Investigation of the biological processes and signaling pathways enriched in each subpopulation revealed that in addition to bone formation, preosteoblasts and undetermined osteoblasts may also regulate both angiogenesis and hemopoiesis. Finally, we demonstrated that there are systematic differences between the transcriptional profiles of human osteoblasts in vivo and mouse osteoblasts both in vivo and in vitro, highlighting the necessity for studying bone physiological processes in humans rather than solely relying on mouse models. Our findings provide novel insights into the cellular heterogeneity and potential biological functions of human primary osteoblasts at the single-cell level, which is an important and necessary step to further dissect the biological roles of osteoblasts in bone metabolism under various (patho-) physiological conditions.

bioinformatics↗

bioRxiv2020

Phytochrome mediated responses in Agrobacterium fabrum: growth, swimming, plant infection and interbacterial competition

The soil bacterium Agrobacterium fabrum C58 infects plants by a unique DNA transfer mechanism. A. fabrum has two phytochrome photoreceptors, Agp1 and Agp2. We found that DNA transfer into plants by A. fabrum is down regulated by light and that phytochrome knockout mutants have diminished DNA transfer rates. The regulation pattern matches with that of bacterial conjugation reported earlier. Growth, swimming and interbacterial competition were also affected in phytochrome knockout mutants, although these effects were often not affected by light. We can thus distinguish between light-regulated and light-independent phytochrome responses. In microarray studies, transcription of only 4 genes was affected by light, indicating that most light responses are regulated post-transcriptionally. In a mass spectrometery-based proteomic study, 24 proteins were different between light and dark grown bacteria, whereas 382 proteins differed between wild type and phytochrome knockout mutants, pointing again to light-dependent and light-independent roles of Agp1 and Agp2.

microbiology↗

bioRxiv2020

Evolution and molecular characteristics of SARS-CoV-2 genome

ObjectivesTo reveal epidemic trend and possible origins of SARS-CoV-2 by exploring its evolution and molecular characteristics based on a large number of genomes since it has infected millions of people and spread quickly all over the world. MethodsVarious evolution analysis methods were employed. ResultsThe estimated Ka/Ks ratio of SARS-CoV-2 is 1.008 or 1.094 based on 622 or 3624 SARS-CoV-2 genomes, and the time to the most recent common ancestor (tMRCA) was inferred in late September 2019. Further 9 key specific sites of highly linkage and four major haplotypes H1, H2, H3 and H4 were found. The Ka/Ks, detected population size and development trends of each major haplotype showed H3 and H4 subgroups were going through a purify evolution and almost disappeared after detection, indicating H3 and H4 might have existed for a long time, while H1 and H2 subgroups were going through a near neutral or neutral evolution and globally increased with time. Notably the frequency of H1 was generally high in Europe and correlated to death rate (r>0.37). ConclusionsIn this study, the evolution and molecular characteristics of more than 16000 genomic sequences provided a new perspective for revealing epidemiology of SARS-CoV-2.

bioinformatics↗

bioRxiv2020

SIRT1 ameliorates premature senescence-induced defenestration in hepatic sinusoidal endothelial cell

Premature senescence, linked to progerin, involves in endothelial dysfunction and liver diseases. Activating sirtuin 1 (SIRT1) ameliorates liver fibrosis. However, the potential mechanisms of premature senescence in defenestration in hepatic sinusoidal endothelial cells (HSECs) and how SIRT1 affects fenestrae remains elusive. Our study showed that in vivo, premature senescence occurred, with decrease of SIRT1, during CCl4-induced defenestration in HSECs and liver fibrogenesis; whereas overexpressing SIRT1 with adenovirus vector lessened progerin-associated premature senescence to relieve CCl4-induced defenestration and liver fibrosis. In vitro, fenestrae in HSECs disappeared, with progerin-associated premature senescence; these effects aggravated by H2O2-induced oxidative damage. Nevertheless, knockdown of NOX2 or overexpression of SIRT1 with adenovirus vector reduced progerin-associated premature senescence to maintain fenestrae through deacetylating p53. Furthermore, more Ac p53 K381 and progerin co-localized with accumulation of actin filament (F-actin) in the nuclear envelope of H2O2-treated HSECs; in contrast, these effects were rescued by overexpressing SIRT1. In conclusion, NOX2-dependent oxidative damage aggravates defenestration in HSECs via progerin-associated premature senescence; SIRT1-mediated deacetylation of p53 maintains fenestrae and attenuates liver fibrogenesis through inhibiting premature senescence.

cell biology↗