scholarly journals Arabinose-Induced Catabolite Repression as a Mechanism for Pentose Hierarchy Control inClostridium acetobutylicumATCC 824

mSystems ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Matthew D. Servinsky ◽  
Rebecca L. Renberg ◽  
Matthew A. Perisin ◽  
Elliot S. Gerlach ◽  
Sanchao Liu ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Genetic Engineering ◽  
Catabolite Repression ◽  
Clostridium Acetobutylicum ◽  
Regulation Mechanism ◽  
Mrna Levels ◽  
Chemical Production ◽  
Content Type ◽  
Commodity Chemicals ◽  
Pentose Utilization

ABSTRACTBacterial fermentation of carbohydrates from sustainable lignocellulosic biomass into commodity chemicals by the anaerobic bacteriumClostridium acetobutylicumis a promising alternative source to fossil fuel-derived chemicals. Recently, it was demonstrated that xylose is not appreciably fermented in the presence of arabinose, revealing a hierarchy of pentose utilization in this organism (L. Aristilde, I. A. Lewis, J. O. Park, and J. D. Rabinowitz, Appl Environ Microbiol 81:1452–1462, 2015,https://doi.org/10.1128/AEM.03199-14). The goal of the current study is to characterize the transcriptional regulation that occurs and perhaps drives this pentose hierarchy. Carbohydrate consumption rates showed that arabinose, like glucose, actively represses xylose utilization in cultures fermenting xylose. Further, arabinose addition to xylose cultures led to increased acetate-to-butyrate ratios, which indicated a transition of pentose catabolism from the pentose phosphate pathway to the phosphoketolase pathway. Transcriptome sequencing (RNA-Seq) confirmed that arabinose addition to cells actively growing on xylose resulted in increased phosphoketolase (CA_C1343) mRNA levels, providing additional evidence that arabinose induces this metabolic switch. A significant overlap in differentially regulated genes after addition of arabinose or glucose suggested a common regulation mechanism. A putative open reading frame (ORF) encoding a potential catabolite repression phosphocarrier histidine protein (Crh) was identified that likely participates in the observed transcriptional regulation. These results substantiate the claim that arabinose is utilized preferentially over xylose inC. acetobutylicumand suggest that arabinose can activate carbon catabolite repression via Crh. Furthermore, they provide valuable insights into potential mechanisms for altering pentose utilization to modulate fermentation products for chemical production.IMPORTANCEClostridium acetobutylicumcan ferment a wide variety of carbohydrates to the commodity chemicals acetone, butanol, and ethanol. Recent advances in genetic engineering have expanded the chemical production repertoire ofC. acetobutylicumusing synthetic biology. Due to its natural properties and genetic engineering potential, this organism is a promising candidate for converting biomass-derived feedstocks containing carbohydrate mixtures to commodity chemicals via natural or engineered pathways. Understanding how this organism regulates its metabolism during growth on carbohydrate mixtures is imperative to enable control of synthetic gene circuits in order to optimize chemical production. The work presented here unveils a novel mechanism via transcriptional regulation by a predicted Crh that controls the hierarchy of carbohydrate utilization and is essential for guiding robust genetic engineering strategies for chemical production.

scholarly journals Iron Regulation through the Back Door: Iron-Dependent Metabolite Levels Contribute to Transcriptional Adaptation to Iron Deprivation in Saccharomyces cerevisiae

2009 ◽  
Vol 9 (3) ◽  
pp. 460-471 ◽  
Author(s):  
Jessica Ihrig ◽  
Anja Hausmann ◽  
Anika Hain ◽  
Nadine Richter ◽  
Iqbal Hamza ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Transcriptional Activation ◽  
Quantitative Description ◽  
Mrna Levels ◽  
Metabolic Intermediate ◽  
Content Type ◽  
Iron Deprivation ◽  
Transcriptional Adaptation

ABSTRACTBudding yeast (Saccharomyces cerevisiae) responds to iron deprivation both by Aft1-Aft2-dependent transcriptional activation of genes involved in cellular iron uptake and by Cth1-Cth2-specific degradation of certain mRNAs coding for iron-dependent biosynthetic components. Here, we provide evidence for a novel principle of iron-responsive gene expression. This regulatory mechanism is based on the modulation of transcription through the iron-dependent variation of levels of regulatory metabolites. As an example, theLEU1gene of branched-chain amino acid biosynthesis is downregulated under iron-limiting conditions through depletion of the metabolic intermediate α-isopropylmalate, which functions as a key transcriptional coactivator of the Leu3 transcription factor. Synthesis of α-isopropylmalate involves the iron-sulfur protein Ilv3, which is inactivated under iron deficiency. As another example, decreased mRNA levels of the cytochromec-encodingCYC1gene under iron-limiting conditions involve heme-dependent transcriptional regulation via the Hap1 transcription factor. Synthesis of the iron-containing heme is directly correlated with iron availability. Thus, the iron-responsive expression of genes that are downregulated under iron-limiting conditions is conferred by two independent regulatory mechanisms: transcriptional regulation through iron-responsive metabolites and posttranscriptional mRNA degradation. Only the combination of the two processes provides a quantitative description of the response to iron deprivation in yeast.

scholarly journals Extending CRISPR-Cas9 Technology from Genome Editing to Transcriptional Engineering in the Genus Clostridium

2016 ◽  
Vol 82 (20) ◽  
pp. 6109-6119 ◽  
Author(s):  
Mark R. Bruder ◽  
Michael E. Pyne ◽  
Murray Moo-Young ◽  
Duane A. Chung ◽  
C. Perry Chou
Keyword(s):  
Genetic Engineering ◽  
Genome Editing ◽  
Transcriptional Repression ◽  
Clostridium Acetobutylicum ◽  
Fluorescent Protein ◽  
Genetic Manipulation ◽  
Carbon Sources ◽  
Anaerobic Bacteria ◽  
Clostridium Pasteurianum ◽  
Content Type

ABSTRACTThe discovery and exploitation of the prokaryotic adaptive immunity system based on clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins have revolutionized genetic engineering. CRISPR-Cas tools have enabled extensive genome editing as well as efficient modulation of the transcriptional program in a multitude of organisms. Progress in the development of genetic engineering tools for the genusClostridiumhas lagged behind that of many other prokaryotes, presenting the CRISPR-Cas technology an opportunity to resolve a long-existing issue. Here, we applied theStreptococcus pyogenestype II CRISPR-Cas9 (SpCRISPR-Cas9) system for genome editing inClostridium acetobutylicumDSM792. We further explored the utility of the SpCRISPR-Cas9 machinery for gene-specific transcriptional repression. For proof-of-concept demonstration, a plasmid-encoded fluorescent protein gene was used for transcriptional repression inC. acetobutylicum. Subsequently, we targeted the carbon catabolite repression (CCR) system ofC. acetobutylicumthrough transcriptional repression of thehprKgene encoding HPr kinase/phosphorylase, leading to the coutilization of glucose and xylose, which are two abundant carbon sources from lignocellulosic feedstocks. Similar approaches based on SpCRISPR-Cas9 for genome editing and transcriptional repression were also demonstrated inClostridium pasteurianumATCC 6013. As such, this work lays a foundation for the derivation of clostridial strains for industrial purposes.IMPORTANCEAfter recognizing the industrial potential ofClostridiumfor decades, methods for the genetic manipulation of these anaerobic bacteria are still underdeveloped. This study reports the implementation of CRISPR-Cas technology for genome editing and transcriptional regulation inClostridium acetobutylicum, which is arguably the most common industrial clostridial strain. The developed genetic tools enable simpler, more reliable, and more extensive derivation ofC. acetobutylicummutant strains for industrial purposes. Similar approaches were also demonstrated inClostridium pasteurianum, another clostridial strain that is capable of utilizing glycerol as the carbon source for butanol fermentation, and therefore can be arguably applied in other clostridial strains.

scholarly journals Novel Transcriptional Regulons for Autotrophic Cycle Genes in Crenarchaeota

2015 ◽  
Vol 197 (14) ◽  
pp. 2383-2391 ◽  
Author(s):  
Semen A. Leyn ◽  
Irina A. Rodionova ◽  
Xiaoqing Li ◽  
Dmitry A. Rodionov
Keyword(s):  
Carbon Dioxide ◽  
Transcriptional Regulation ◽  
Comparative Genomics ◽  
Dna Binding ◽  
Transcriptional Control ◽  
Binding Assays ◽  
Promoter Regions ◽  
Content Type ◽  
Genome Context

ABSTRACTAutotrophic microorganisms are able to utilize carbon dioxide as their only carbon source, or, alternatively, many of them can grow heterotrophically on organics. Different variants of autotrophic pathways have been identified in various lineages of the phylumCrenarchaeota. Aerobic members of the orderSulfolobalesutilize the hydroxypropionate-hydroxybutyrate cycle (HHC) to fix inorganic carbon, whereas anaerobicThermoprotealesuse the dicarboxylate-hydroxybutyrate cycle (DHC). Knowledge of transcriptional regulation of autotrophic pathways inArchaeais limited. We applied a comparative genomics approach to predict novel autotrophic regulons in theCrenarchaeota. We report identification of two novel DNA motifs associated with the autotrophic pathway genes in theSulfolobales(HHC box) andThermoproteales(DHC box). Based on genome context evidence, the HHC box regulon was attributed to a novel transcription factor from the TrmB family named HhcR. Orthologs of HhcR are present in allSulfolobalesgenomes but were not found in other lineages. A predicted HHC box regulatory motif was confirmed byin vitrobinding assays with the recombinant HhcR protein fromMetallosphaera yellowstonensis. For the DHC box regulon, we assigned a different potential regulator, named DhcR, which is restricted to the orderThermoproteales. DhcR inThermoproteus neutrophilus(Tneu_0751) was previously identified as a DNA-binding protein with high affinity for the promoter regions of two autotrophic operons. The global HhcR and DhcR regulons reconstructed by comparative genomics were reconciled with available omics data inMetallosphaeraandThermoproteusspp. The identified regulons constitute two novel mechanisms for transcriptional control of autotrophic pathways in theCrenarchaeota.IMPORTANCELittle is known about transcriptional regulation of carbon dioxide fixation pathways inArchaea. We previously applied the comparative genomics approach for reconstruction of DtxR family regulons in diverse lineages ofArchaea. Here, we utilize similar computational approaches to identify novel regulatory motifs for genes that are autotrophically induced in microorganisms from two lineages ofCrenarchaeotaand to reconstruct the respective regulons. The predicted novel regulons in archaeal genomes control the majority of autotrophic pathway genes and also other carbon and energy metabolism genes. The HhcR regulon was experimentally validated by DNA-binding assays inMetallosphaeraspp. Novel regulons described for the first time in this work provide a basis for understanding the mechanisms of transcriptional regulation of autotrophic pathways inArchaea.

scholarly journals A Novel Position-Specific Encoding Algorithm (SeqPose) of Nucleotide Sequences and Its Application for Detecting Enhancers

2021 ◽  
Vol 22 (6) ◽  
pp. 3079
Author(s):  
Xuechen Mu ◽  
Yueying Wang ◽  
Meiyu Duan ◽  
Shuai Liu ◽  
Fei Li ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Dna Sequence ◽  
Prediction Models ◽  
Nucleotide Sequences ◽  
Attention Mechanism ◽  
Training Dataset ◽  
Regulation Mechanism ◽  
Independent Test ◽  
Regulation Strength ◽  
Enhancer Detection

Enhancers are short genomic regions exerting tissue-specific regulatory roles, usually for remote coding regions. Enhancers are observed in both prokaryotic and eukaryotic genomes, and their detections facilitate a better understanding of the transcriptional regulation mechanism. The accurate detection and transcriptional regulation strength evaluation of the enhancers remain a major bioinformatics challenge. Most of the current studies utilized the statistical features of short fixed-length nucleotide sequences. This study introduces the location information of each k-mer (SeqPose) into the encoding strategy of a DNA sequence and employs the attention mechanism in the two-layer bi-directional long-short term memory (BD-LSTM) model (spEnhancer) for the enhancer detection problem. The first layer of the delivered classifier discriminates between enhancers and non-enhancers, and the second layer evaluates the transcriptional regulation strength of the detected enhancer. The SeqPose-encoded features are selected by the Chi-squared test, and 45 positions are removed from further analysis. The existing studies may focus on selecting the statistical DNA sequence descriptors with large contributions to the prediction models. This study does not utilize these statistical DNA sequence descriptors. Then the word vector of the SeqPose-encoded features is obtained by using the word embedding layer. This study hypothesizes that different word vector features may contribute differently to the enhancer detection model, and assigns different weights to these word vectors through the attention mechanism in the BD-LSTM model. The previous study generously provided the training and independent test datasets, and the proposed spEnhancer is compared with the three existing state-of-the-art studies using the same experimental procedure. The leave-one-out validation data on the training dataset shows that the proposed spEnhancer achieves similar detection performances as the three existing studies. While spEnhancer achieves the best overall performance metric MCC for both of the two binary classification problems on the independent test dataset. The experimental data shows that the strategy of removing redundant positions (SeqPose) may help improve the DNA sequence-based prediction models. spEnhancer may serve well as a complementary model to the existing studies, especially for the novel query enhancers that are not included in the training dataset.

scholarly journals Natural Disruption of Two Regulatory Networks in Serotype M3 Group A Streptococcus Isolates Contributes to the Virulence Factor Profile of This Hypervirulent Serotype

2014 ◽  
Vol 82 (5) ◽  
pp. 1744-1754 ◽  
Author(s):  
Tram N. Cao ◽  
Zhuyun Liu ◽  
Tran H. Cao ◽  
Kathryn J. Pflughoeft ◽  
Jeanette Treviño ◽  
...  
Keyword(s):  
Virulence Factor ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Group A Streptococcus ◽  
Regulatory System ◽  
Mrna Levels ◽  
Bacterial Strains ◽  
Content Type ◽  
Small Regulatory Rna ◽  
Group A

ABSTRACTDespite the public health challenges associated with the emergence of new pathogenic bacterial strains and/or serotypes, there is a dearth of information regarding the molecular mechanisms that drive this variation. Here, we began to address the mechanisms behind serotype-specific variation between serotype M1 and M3 strains of the human pathogenStreptococcus pyogenes(the group AStreptococcus[GAS]). Spatially diverse contemporary clinical serotype M3 isolates were discovered to contain identical inactivating mutations within genes encoding two regulatory systems that control the expression of important virulence factors, including the thrombolytic agent streptokinase, the protease inhibitor-binding protein-G-related α2-macroglobulin-binding (GRAB) protein, and the antiphagocytic hyaluronic acid capsule. Subsequent analysis of a larger collection of isolates determined that M3 GAS, since at least the 1920s, has harbored a 4-bp deletion in thefasCgene of thefasBCAXregulatory system and an inactivating polymorphism in therivRregulator-encoding gene. ThefasCandrivRmutations in M3 isolates directly affect the virulence factor profile of M3 GAS, as evident by a reduction in streptokinase expression and an enhancement of GRAB expression. Complementation of thefasCmutation in M3 GAS significantly enhanced levels of the small regulatory RNA FasX, which in turn enhanced streptokinase expression. Complementation of therivRmutation in M3 GAS restored the regulation ofgrabmRNA abundance but did not alter capsule mRNA levels. While important, thefasCandrivRmutations do not provide a full explanation for why serotype M3 strains are associated with unusually severe invasive infections; thus, further investigation is warranted.

Phenobarbital inhibits calpain activity and expression in mouse hepatoma cells

2016 ◽  
Vol 397 (1) ◽  
pp. 91-96 ◽  
Author(s):  
Nicola Groll ◽  
Ferdinand Kollotzek ◽  
Jens Goepfert ◽  
Thomas O. Joos ◽  
Michael Schwarz ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Regulation ◽  
Antiepileptic Drug ◽  
Signaling Pathway ◽  
Constitutive Androstane Receptor ◽  
Hepatoma Cells ◽  
Liver Cells ◽  
Mrna Levels ◽  
Calpain Activity ◽  
Mouse Hepatoma

Abstract The antiepileptic drug phenobarbital (PB) exerts hepatic effects related to cell proliferation and tumorigenesis which are closely linked to the Wnt/β-catenin signaling pathway. This pathway is, amongst others, regulated by calpain proteases. We now identified PB as an inhibitor of Wnt/β-catenin signaling in mouse hepatoma cells. Further analyses revealed that PB inhibits calpain activity, an effect which is at least in parts mediated by a transcriptional regulation of calpain mRNA levels and which is furthermore independent of the constitutive androstane receptor, the known mediator of most effects of PB in liver cells.

The Corfu δβ thalassemia deletion disrupts γ-globin gene silencing and reveals post-transcriptional regulation of HbF expression

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2154-2160 ◽  
Author(s):  
Lyubomira Chakalova ◽  
Cameron S. Osborne ◽  
Yan-Feng Dai ◽  
Beatriz Goyenechea ◽  
Anna Metaxotou-Mavromati ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Gene Transcription ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Critical Threshold ◽  
Critical Element ◽  
Mrna Levels ◽  
Globin Genes ◽  
Mrna Accumulation ◽  
Post Transcriptional Regulation

Abstract The 7.2 kilobase (kb) Corfu δβ thalassemia mutation is the smallest known deletion encompassing a region upstream of the human δ gene that has been suggested to account for the vastly different phenotypes in hereditary persistence of fetal hemoglobin (HPFH) versus β thalassemia. Fetal hemoglobin (HbF) expression in Corfu heterozygotes and homozygotes is paradoxically dissimilar, suggesting conflicting theories as to the function of the region on globin gene regulation. Here, we measure γ- and β-globin gene transcription, steady-state mRNA, and hemoglobin expression levels in primary erythroid cells cultured from several patients with Corfu δβ thalassemia. We show through RNA fluorescence in situ hybridization that the Corfu deletion results in high-level transcription of the fetal γ genes in cis with a concomitant reduction in transcription of the downstream β gene. Surprisingly, we find that elevated γ gene transcription does not always result in a corresponding accumulation of γ mRNA or fetal hemoglobin, indicating a post-transcriptional regulation of γ gene expression. The data suggest that efficient γ mRNA accumulation and HbF expression are blocked until β mRNA levels fall below a critical threshold. These results explain the Corfu paradox and show that the deleted region harbors a critical element that functions in the developmentally regulated transcription of the β-globin genes.

scholarly journals Substrate-Induced Production and Secretion of Cellulases by Clostridium acetobutylicum

2004 ◽  
Vol 70 (9) ◽  
pp. 5238-5243 ◽  
Author(s):  
Ana M. López-Contreras ◽  
Krisztina Gabor ◽  
Aernout A. Martens ◽  
Bernadet A. M. Renckens ◽  
Pieternel A. M. Claassen ◽  
...  
Keyword(s):  
Catabolite Repression ◽  
Clostridium Acetobutylicum ◽  
Glycoside Hydrolase ◽  
Protein A ◽  
Cellulase Activity ◽  
Glycoside Hydrolase Family ◽  
Extracellular Production ◽  
Encoding Genes ◽  
Glycoside Hydrolase Family 48 ◽  
Hydrolase Family

ABSTRACT Clostridium acetobutylicum ATCC 824 is a solventogenic bacterium that grows heterotrophically on a variety of carbohydrates, including glucose, cellobiose, xylose, and lichenan, a linear polymer of β-1,3- and β-1,4-linked β-d-glucose units. C. acetobutylicum does not degrade cellulose, although its genome sequence contains several cellulase-encoding genes and a complete cellulosome cluster of cellulosome genes. In the present study, we demonstrate that a low but significant level of induction of cellulase activity occurs during growth on xylose or lichenan. The celF gene, located in the cellulosome-like gene cluster and coding for a unique cellulase that belongs to glycoside hydrolase family 48, was cloned in Escherichia coli, and antibodies were raised against the overproduced CelF protein. A Western blot analysis suggested a possible catabolite repression by glucose or cellobiose and an up-regulation by lichenan or xylose of the extracellular production of CelF by C. acetobutylicum. Possible reasons for the apparent inability of C. acetobutylicum to degrade cellulose are discussed.

scholarly journals Downregulation of the Central Noradrenergic System by Toxoplasma gondii Infection

2018 ◽  
Vol 87 (2) ◽  
Author(s):  
Isra Alsaady ◽  
Ellen Tedford ◽  
Mohammad Alsaad ◽  
Greg Bristow ◽  
Shivali Kohli ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Infection Intensity ◽  
Noradrenergic System ◽  
Neural Cells ◽  
Mrna Levels ◽  
Female Rat ◽  
Motor Impairments ◽  
Content Type ◽  
General Response

ABSTRACT Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro. The mechanism responsible for the NE suppression was found to be downregulation of dopamine β-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine, with downregulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The downregulation was sex specific, with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection, as human cytomegalovirus did not downregulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels, which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioral effects of infection and associations with mental illness.

scholarly journals A cell cycle analysis of growth-related genes expressed during T lymphocyte maturation.

1990 ◽  
Vol 111 (6) ◽  
pp. 2693-2701 ◽  
Author(s):  
J N Feder ◽  
C J Guidos ◽  
B Kusler ◽  
C Carswell ◽  
D Lewis ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Regulation ◽  
Steady State ◽  
T Lymphocyte ◽  
Ribonucleotide Reductase ◽  
Cellular Proliferation ◽  
Rnase Protection Assay ◽  
Minor Component ◽  
Mrna Levels ◽  
Rnase Protection

Fetal liver or bone marrow-derived T lymphocyte precursors undergo extensive, developmentally regulated proliferation in response to inductive signals from the thymic microenvironment. We have used neonatal mouse thymocytes size-separated by centrifugal elutriation to study the cell cycle stage-specific expression of several genes associated with cell proliferation. These include genes involved in the biosynthesis of deoxyribonucleotide precursors, such as dihydrofolate reductase (DHFR), thymidylate synthase (TS), and the M1 and M2 subunits of ribonucleotide reductase, as well as c-myc, a cellular oncogene of unknown function. Using nuclear run-on assays, we observed that the transcription rates for these genes, with the exception of TS, are essentially invariant not only throughout the cell cycle in proliferating cells, but also in noncycling (G0) cells. The TS gene showed a transient increase in transcription rate in cells which bordered between a proliferating and nonproliferating status. Studies of an elutriated T cell line, S49.1, yielded similar results, indicating that the process of immortalization has not affected the transcriptional regulation of these genes. Analysis of steady-state mRNA levels using an RNase protection assay demonstrated that the levels of DHFR and TS mRNA accumulate as thymocytes progress through the cell cycle. In contrast, only the M2 subunit of ribonucleotide reductase showed cyclic regulation. Finally, in contrast to cultured cell models, we observed an abrupt fivefold increase in the steady-state level of c-myc mRNA in the transition from G1 to S-phase. We conclude from these studies that the transcriptional regulation of specific genes necessary for cellular proliferation is a minor component of the developmental modulation of the thymocyte cell cycle.

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