scholarly journals Bioinformatics analysis and collection of protein post-translational modification sites in human viruses

2020 ◽  
Author(s):  
Yujia Xiang ◽  
Quan Zou ◽  
Lilin Zhao
Keyword(s):  
Viral Protein ◽  
Protein Modification ◽  
Phosphorylation Site ◽  
Protein Domains ◽  
Human Interaction ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Human Proteins ◽  
Human Viruses

AbstractIn viruses, post-translational modifications (PTMs) are essential for their life cycle. Recognizing viral PTMs is very important for better understanding the mechanism of viral infections and finding potential drug targets. However, few studies have investigated the roles of viral PTMs in virus-human interactions using comprehensive viral PTM datasets. To fill this gap, firstly, we developed a viral post-translational modification database (VPTMdb) for collecting systematic information of viral PTM data. The VPTMdb contains 912 PTM sites that integrate 414 experimental-confirmed PTM sites with 98 proteins in 45 human viruses manually extracted from 162 publications and 498 PTMs extracted from UniProtKB/Swiss-Prot. Secondly, we investigated the viral PTM sequence motifs, the function of target human proteins, and characteristics of PTM protein domains. The results showed that (i) viral PTMs have the consensus motifs with human proteins in phosphorylation, SUMOylation and N-glycosylation. (ii) The function of human proteins that targeted by viral PTM proteins are related to protein targeting, translation, and localization. (iii) Viral PTMs are more likely to be enriched in protein domains. The findings should make an important contribution to the field of virus-human interaction. Moreover, we created a novel sequence-based classifier named VPTMpre to help users predict viral protein phosphorylation sites. Finally, an online web server was implemented for users to download viral protein PTM data and predict phosphorylation sites of interest.Author summaryPost-translational modifications (PTMs) plays an important role in the regulation of viral proteins; However, due to the limitation of data sets, there has been no detailed investigation of viral protein PTMs characteristics. In this manuscript, we collected experimentally verified viral protein post-translational modification sites and analysed viral PTMs data from a bioinformatics perspective. Besides, we constructed a novel feature-based machine learning model for predicting phosphorylation site. This is the first study to explore the roles of viral protein modification in virus infection using computational methods. The valuable viral protein PTM data resource will provide new insights into virus-host interaction.

scholarly journals VPTMdb: a viral posttranslational modification database

2020 ◽  
Author(s):  
Yujia Xiang ◽  
Quan Zou ◽  
Lilin Zhao
Keyword(s):  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Drug Targets ◽  
Viral Infections ◽  
Interaction Analysis ◽  
Human Interaction ◽  
Host Cells ◽  
Phosphorylation Sites ◽  
Human Viruses ◽  
Disordered Regions

Abstract In viruses, posttranslational modifications (PTMs) are essential for their life cycle. Recognizing viral PTMs is very important for a better understanding of the mechanism of viral infections and finding potential drug targets. However, few studies have investigated the roles of viral PTMs in virus–human interactions using comprehensive viral PTM datasets. To fill this gap, we developed the first comprehensive viral posttranslational modification database (VPTMdb) for collecting systematic information of PTMs in human viruses and infected host cells. The VPTMdb contains 1240 unique viral PTM sites with 8 modification types from 43 viruses (818 experimentally verified PTM sites manually extracted from 150 publications and 422 PTMs extracted from SwissProt) as well as 13 650 infected cells’ PTMs extracted from seven global proteomics experiments in six human viruses. The investigation of viral PTM sequences motifs showed that most viral PTMs have the consensus motifs with human proteins in phosphorylation and five cellular kinase families phosphorylate more than 10 viral species. The analysis of protein disordered regions presented that more than 50% glycosylation sites of double-strand DNA viruses are in the disordered regions, whereas single-strand RNA and retroviruses prefer ordered regions. Domain–domain interaction analysis indicating potential roles of viral PTMs play in infections. The findings should make an important contribution to the field of virus–human interaction. Moreover, we created a novel sequence-based classifier named VPTMpre to help users predict viral protein phosphorylation sites. VPTMdb online web server (http://vptmdb.com:8787/VPTMdb/) was implemented for users to download viral PTM data and predict phosphorylation sites of interest.

scholarly journals A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Ebru Ercan-Herbst ◽  
Jens Ehrig ◽  
David C. Schöndorf ◽  
Annika Behrendt ◽  
Bernd Klaus ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Small Set ◽  
Human Brains

AbstractTau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0–I, II or III–IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III–IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

DIABETES-POST-TRANSLATIONAL PROTEIN MODIFICATION FOR DEVELOPMENT OF NEW DRUGS

INDIAN DRUGS ◽  
2014 ◽  
Vol 51 (09) ◽  
pp. 5-11
Author(s):  
P Menon ◽  
◽  
M S Kumar
Keyword(s):  
Glucose Level ◽  
Protein Modification ◽  
Epigenetic Modification ◽  
The Body ◽  
New Drugs ◽  
Metabolic Memory ◽  
Peroxisome Proliferator ◽  
Post Translational Modification ◽  
High Molecular Weight Adiponectin ◽  
Post Translational Modifications

Diabetes is a disorder associated with improper use of glucose by the body leading to increased level of glucose in the blood stream. Beta cells in the pancreas produce the hormone insulin, which is responsible for the movement of glucose into cells where it is utilized to produce energy. Due to the shortage of insulin in diabetic condition, the level of glucose in the bloodstream increases. The level of glucose within cells fall and thus the cells are not able to produce energy using glucose. It also gives rise to various other complications such as blindness, kidney failure, numbness in toes, delayed wound healing, cardiovascular complications, weight gain, loss of consciousness, disorientation etc. which in itself may be dangerous. The root cause of diabetes may either be lack of insulin being produced by the pancreas or development of resistance towards insulin leading to no effect of insulin on the glucose level. Post-translational modifications of protein control various biological processes. It is also considered as an important process in the pathogenesis of diabetes mellitus.In the current review, we will discuss the recent developments in post translational modification of genes associated with diabetes as well as epigenetic modification and metabolic memory that maybe responsible for the onset of diabetes and its associated complications. Currently research is being conducted on high molecular weight adiponectin, peroxisome proliferator-activated receptors (PPARγ), epigenetic histone modifications and Calpain 10 (CAPN10 gene encoded) protein based upon the post translational modifications they undergo and how these modifications affect glucose level regulation. This review article aims at shedding light upon recent advances in biotechnology that are focussed on studying the nature of protein modifications that result in diabetes and finding ways to prevent these modifications or stimulate a new modification that may result in better control of the disease state if not a cure.

scholarly journals Characterization of intron 7 to exon 8 of heat shock protein 90-aa1 (hsp90aa1) gene in dominant brown layer chicken using some bioinformatic tools

2021 ◽  
Vol 78 (2) ◽  
pp. 55
Author(s):  
Young IRIVBOJE ◽  
Adeboye FAFIOLU ◽  
Oluwabusayo IRIVBOJE ◽  
Christian IKEOBI
Keyword(s):  
Heat Stress ◽  
Secondary Structure ◽  
Homology Modelling ◽  
Phosphorylation Site ◽  
Evolutionary Relationship ◽  
Structural Features ◽  
Avian Species ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Relationship Study

HSP90AA1, an isoform of HSP90 has been characterized to indicate it plays important roles in basic cellular events. It is activated in chicken in response to heat stress. This study was aimed at the computational analysis of the biochemical cum structural features and an evolutionary relationship study on the HSP90AA1 gene in Dominant brown layers (DBL) and some selected avian species using bioinformatics tools. ProtParam for physicochemical properties. Scanprosite for post-translational modification sites, Netphos-3.1 for phosphorylation sites, BDM-PUB program for Ubiquitination sites, PDBSUM for Secondary structure and homology modelling with SWISS-model. The findings revealed that intron 7 and exon 8 of HSP90AA1 protein in DBL had a molecular weight of 24681.19Da and an instability index of 27.60, contains N-myristoylation, Protein-kinase-C-phosphorylation and Tyrosine-kinase-phosphorylation site-2 post-translational modification sites, 4-serine and 2-threonine phosphorylation sites and 12-ubiquitination sites. The evolutionary relationship study found Japanese quail to be in a sister branch close to DBL and chicken. Motifs detected in the avian species revealed the gene to be highly conserved. The secondary structure consisted of 16-helices, 3-sheets and 14-strands. The homology modelling was 87.25% sequence identity with human MC-HSP90-alpha. The study elucidates the components and characteristics of HSP90AA1 in DBL in response to heat stress.

scholarly journals DeepPhos: prediction of protein phosphorylation sites with deep learning

2019 ◽  
Vol 35 (16) ◽  
pp. 2766-2773 ◽  
Author(s):  
Fenglin Luo ◽  
Minghui Wang ◽  
Yu Liu ◽  
Xing-Ming Zhao ◽  
Ao Li
Keyword(s):  
Deep Learning ◽  
Protein Phosphorylation ◽  
Phosphorylation Site ◽  
Supplementary Information ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Neuron Network ◽  
Site Prediction ◽  
Specific Prediction ◽  
Group Family

Abstract Motivation Phosphorylation is the most studied post-translational modification, which is crucial for multiple biological processes. Recently, many efforts have been taken to develop computational predictors for phosphorylation site prediction, but most of them are based on feature selection and discriminative classification. Thus, it is useful to develop a novel and highly accurate predictor that can unveil intricate patterns automatically for protein phosphorylation sites. Results In this study we present DeepPhos, a novel deep learning architecture for prediction of protein phosphorylation. Unlike multi-layer convolutional neural networks, DeepPhos consists of densely connected convolutional neuron network blocks which can capture multiple representations of sequences to make final phosphorylation prediction by intra block concatenation layers and inter block concatenation layers. DeepPhos can also be used for kinase-specific prediction varying from group, family, subfamily and individual kinase level. The experimental results demonstrated that DeepPhos outperforms competitive predictors in general and kinase-specific phosphorylation site prediction. Availability and implementation The source code of DeepPhos is publicly deposited at https://github.com/USTCHIlab/DeepPhos. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals A post-translational modification of the sheath modulatesFrancisellatype VI secretion system assembly and function

2018 ◽  
Author(s):  
Jason Ziveri ◽  
Cerina Chhuon ◽  
Anne Jamet ◽  
Guénolé Prigent ◽  
Héloïse Rytter ◽  
...  
Keyword(s):  
Critical Role ◽  
Phosphorylation Site ◽  
Post Translational Modification ◽  
Secretion Systems ◽  
Post Translational Modifications ◽  
Type Vi Secretion ◽  
Sheath Formation ◽  
Canonical Type ◽  
The Stability ◽  
And Function

AbstractFrancisella tularensisis a facultative intracellular pathogen that causes the zoonotic disease tularemia in human and animal hosts. This bacterium possesses a non-canonical type VI secretion systems (T6SS) required for phagosomal escape and access to its replicative niche in the cytosol of infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the Francisella T6SS in culture. We found that the amounts of essentially all the TSS6 proteins remained unchanged upon KCl stimulation. We therefore hypothesized that a post-translational modification might be involved in T6SS assembly. A whole cell phosphoproteomic analysis allowed us to identify a unique phosphorylation site on IglB, the TssC homologue and key component of the T6SS sheath. Importantly, the phosphorylated form of IglB was not present in the contracted sheath and 3D modeling indicated that the charge repulsion provoked by addition of a phosphogroup on tyrosine 139 was likely to weaken the stability of the sheath structure. Substitutions of the phosphorylatable residue of IglB (tyrosine 139) with alanine or with phosphomimetics prevented T6SS formation and totally impaired phagosomal escape. In contrast, the substitution with the non-phosphorylatable aromatic analog phenylalanine impaired but did not prevent phagosomal escape and cytosolic bacterial multiplication in J774-1 macrophages. Altogether these data suggest that phosphorylation of the sheath participates to T6SS disassembly. Post-translational modifications of the sheath may represent a previously unrecognized mechanism to finely modulate the dynamics of T6SS assembly-disassembly.Data are available via ProteomeXchange with identifier PXD012507.SynopsisFrancisellapossesses a non-canonical T6SS that is essential for efficient phagosomal escape and access to the cytosol of infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the Francisella T6SS in culture. We found that KCl stimulation did not result in an increased production of TSS6 proteins. We therefore hypothesized that a post-translational modification might be involved in T6SS assembly. Using a global and site-specific phosphoproteomic analysis ofFrancisellawe identified a unique phosphorylation site on IglB, the TssC homologue and a key component of the T6SS contractile sheath. We show that this site plays a critical role in T6SS biogenesis and propose that phosphorylation may represent a new mechanism affecting the dynamics of sheath formation.

scholarly journals SKIPHOS: non-kinase specific phosphorylation site prediction with random forests and amino acid skip-gram embeddings

2019 ◽  
Author(s):  
Thanh Hai Dang ◽  
Quang Thinh Trac ◽  
Huy Kinh Phan ◽  
Manh Cuong Nguyen ◽  
Quynh Trang Pham Thi
Keyword(s):  
Prediction Model ◽  
Random Forests ◽  
Protein Modification ◽  
Prediction Models ◽  
Phosphorylation Site ◽  
Supplementary Information ◽  
Phosphorylation Sites ◽  
Site Prediction ◽  
Link Type ◽  
Development And Aging

AbstractMotivationPhosphorylation, which is catalyzed by kinase proteins, is in the top two most common and widely studied types of known essential post-translation protein modification (PTM). Phosphorylation is known to regulate most cellular processes such as protein synthesis, cell division, signal transduction, cell growth, development and aging. Various phosphorylation site prediction models have been developed, which can be broadly categorized as being kinase-specific or non-kinase specific (general). Unlike the latter, the former requires a large enough number of experimentally known phosphorylation sites annotated with a given kinase for training the model, which is not the case in reality: less than 3% of the phosphorylation sites known to date have been annotated with a responsible kinase. To date, there are a few non-kinase specific phosphorylation site prediction models proposed.ResultsThis paper proposes SKIPHOS, a non-kinase specific phosphorylation site prediction model based on random forests on top of a continuous distributed representation of amino acids. Experimental results on the benchmark dataset and the independent test set demonstrate that SKIPHOS compares favorably to recent state-of-the-art related methods for three phosphorylation residues. Although being trained on phosphorylation sites in mamals, SKIPHOS can yield predictions for Y residues better than PHOSFER, a recently proposed plants-specific phosphorylation prediction model.Availability and ImplementationSKIPHOS Web Server is freely available for non-commercial use at http://fit.uet.vnu.edu.vn/SKIPHOS or http://112.137.130.46:[email protected] informationSupplementary data are available at Bioinformatics online.

EPSD: a well-annotated data resource of protein phosphorylation sites in eukaryotes

2020 ◽  
Author(s):  
Shaofeng Lin ◽  
Chenwei Wang ◽  
Jiaqi Zhou ◽  
Ying Shi ◽  
Chen Ruan ◽  
...  
Keyword(s):  
Protein Phosphorylation ◽  
Phosphorylation Site ◽  
Model Organisms ◽  
Functional Domain ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Structural Annotation ◽  
Data Resource ◽  
Protein Protein Interaction ◽  
Almost All

Abstract As an important post-translational modification (PTM), protein phosphorylation is involved in the regulation of almost all of biological processes in eukaryotes. Due to the rapid progress in mass spectrometry-based phosphoproteomics, a large number of phosphorylation sites (p-sites) have been characterized but remain to be curated. Here, we briefly summarized the current progresses in the development of data resources for the collection, curation, integration and annotation of p-sites in eukaryotic proteins. Also, we designed the eukaryotic phosphorylation site database (EPSD), which contained 1 616 804 experimentally identified p-sites in 209 326 phosphoproteins from 68 eukaryotic species. In EPSD, we not only collected 1 451 629 newly identified p-sites from high-throughput (HTP) phosphoproteomic studies, but also integrated known p-sites from 13 additional databases. Moreover, we carefully annotated the phosphoproteins and p-sites of eight model organisms by integrating the knowledge from 100 additional resources that covered 15 aspects, including phosphorylation regulator, genetic variation and mutation, functional annotation, structural annotation, physicochemical property, functional domain, disease-associated information, protein-protein interaction, drug-target relation, orthologous information, biological pathway, transcriptional regulator, mRNA expression, protein expression/proteomics and subcellular localization. We anticipate that the EPSD can serve as a useful resource for further analysis of eukaryotic phosphorylation. With a data volume of 14.1 GB, EPSD is free for all users at http://epsd.biocuckoo.cn/.

Data analysis and prediction of protein posttranslational modification

2014 ◽  
Author(s):  
◽  
Qiuming Yao
Keyword(s):  
Mass Spectrometry ◽  
Protein Phosphorylation ◽  
Posttranslational Modification ◽  
Experimental Approach ◽  
High Resolution Mass Spectrometry ◽  
Phosphorylation Site ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Substrate Network ◽  
Resolution Mass

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Protein posttranslational modification (PTM) occurs broadly after or during protein biosynthesis, to assist folding or activate function during the protein lifetime. Among all types of PTMs, protein phosphorylation is widely recognized as the most pervasive, enzyme-catalyzed post-translational modification in eukaryotes. In particular, plants have higher magnitude of this signaling mechanism in terms of the protein kinase frequency within the genome compared to other eukaryotes. Phosphorylation site mapping using high-resolution mass spectrometry has grown exponentially. In Arabidopsis alone there are thousands of experimentally-determined phosphorylation sites. Likewise, other types of post translational modification data are rapidly increasing too. Acetylation proteome is another big data set in PTM kingdom. To provide an easy access of these modification events in a user-intuitive format we have developed P3DB, The Plant Protein Phosphorylation Database (p3db.org). This database is a repository for plant protein phosphorylation site data. These data can be queried for a protein-of-interest using an integrated BLAST function to search for similar sequences with known phosphorylation sites among the multiple plants currently investigated. Thus, this resource can help identify functionally-conserved phosphorylation sites in plants using a multi-system approach. Centralized by these phosphorylation data, multiple related data and annotations are provided, including protein-protein interaction (PPI), gene ontology, protein tertiary structures, orthologous sequences, kinase/phosphatase classification and Kinase Client Assay (KiC Assay) data. P3DB thus is not only a repository, but also a context provider for studying phosphorylation events. In addition, P3DB incorporates multiple network viewers for the above features, such as PPI network, kinase-substrate network, phosphatase-substrate network, and domain co-occurrence network to help study phosphorylation from a systems point of view. Furthermore, P3DB reflects a community-based design through which users can share data sets and automate data depository processes for publication purposes. Since P3DB is a comprehensive, systematic, and interactive platform for phosphoproteomics research, many data analyses can be done based on it. For example, the disorder analysis and the sequence conservation can be done based on the P3DB datasets. Many researchers downloaded and did some meaningful analysis based on P3DB infrastructure. Although with the development of the high-resolution mass spectrometry protein phosphorylation sites can be reliably identified, the experimental approach is time-consuming and resource-dependent. Furthermore, it is unlikely that an experimental approach could catalog an entire phosphoproteome. Computational prediction of phosphorylation sites provides an efficient and flexible way to reveal potential phosphorylation sites, facilitate experimental phosphorylation site identification and provide hypotheses in experimental design. Musite is a powerful tool that we developed to predict phosphorylation sites based solely on protein sequence. Musite integrates data preprocessing, feature extraction, machine-learning method, and prediction models into one comprehensive tool. Musite (http://musite.net) can be extended to all types of post translational modification study, as long as the dataset contains sufficient modification sites. To further improve the performance of Musite, a generalized motif tree applying fuzzy logic is introduced to compensate the machine learning based prediction. On one hand, using a tree based approach and fuzzy variables help to interpret the final rules, in order to help biologists to obtain the significant patterns. On the other hand, its extracted rule sets essentially generalize the motifs and reveal more information. It can be paired with traditional classification method and provide better interpretation, pre-filtering and analyzing power. Comparing to traditional motif extraction, the fuzzy motif decision tree is able to borrow more information from the observations and thus it may extract more novel motifs or more comprehensive patterns. It can be applied on kinase specific phosphorylated peptides to achieve more insights of the phosphorylation events. A comprehensive database (P3DB), a well-developed prediction tool (Musite), and a generalized motif constructor (Fuzzy Motif Tree) combined enable researchers to investigate the phosphorylation and other posttranslational modification events more thoroughly and thus to reveal more underlying biological significance by applying these computational resources.

scholarly journals A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

2019 ◽  
Author(s):  
Ebru Ercan-Herbst ◽  
David C. Schöndorf ◽  
Annika Behrendt ◽  
Bernd Klaus ◽  
Borja Gomez Ramos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Small Set ◽  
Human Brains

AbstractTau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0-I, II or III-IV, respectively, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We find that soluble tau oligomers are strongly increased at Braak stages III-IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau oligomerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble oligomers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs and shed light on early PTM changes of tau during AD pathogenesis in human brains.

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