The RNA-dependent DNA methylation pathway is required to restrict SPOROCYTELESS/NOZZLE expression to specify a single female germ cell precursor in Arabidopsis

ABSTRACTIn higher plants, the female germline is formed from the megaspore mother cell (MMC), a single cell in the premeiotic ovule. Previously, it was reported that mutants in the RNA-dependent DNA methylation (RdDM) pathway might be involved in restricting the female germline to a single nucellus cell. We show that the DRM methyltransferase double mutant drm1drm2 also presents ectopic enlarged cells, consistent with supernumerary MMC-like cells. In wild-type ovules, MMC differentiation requires SPOROCYTELESS/NOZZLE (SPL/NZZ), as demonstrated by the spl/nzz mutant failing to develop an MMC. We address the poorly understood upstream regulation of SPL/NZZ in ovules, showing that the RdDM pathway is important to restrict SPL/NZZ expression. In ago9, rdr6 and drm1drm2 mutants, SPL/NZZ is expressed ectopically, suggesting that the multiple MMC-like cells observed might be attributable to the ectopic expression of SPL/NZZ. We show that the ovule identity gene, SEEDSTICK, directly regulates AGO9 and RDR6 expression in the ovule and therefore indirectly regulates SPL/NZZ expression. A model is presented describing the network required to restrict SPL/NZZ expression to specify a single MMC.

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STY1 and STY2 promote the formation of apical tissues during Arabidopsis gynoecium development

Development ◽

10.1242/dev.129.20.4707 ◽

2002 ◽

Vol 129 (20) ◽

pp. 4707-4717 ◽

Cited By ~ 1

Author(s):

Sandra Kuusk ◽

Joel J. Sohlberg ◽

Jeff A. Long ◽

Ingela Fridborg ◽

Eva Sundberg

Keyword(s):

Double Mutant ◽

Ectopic Expression ◽

Ring Finger ◽

Regional Differentiation ◽

35S Promoter ◽

Insertion Mutation ◽

Wild Type ◽

Transposon Insertion ◽

Visible Effect ◽

Gynoecium Development

Gynoecium ontogenesis in Arabidopsis is accomplished by the co-ordinated activity of genes that control patterning and the regional differentiation of tissues, and ultimately results in the formation of a basal ovary, a short style and an apical stigma. A transposon insertion in the STYLISH1 (STY1) gene results in gynoecia with aberrant style morphology, while an insertion mutation in the closely related STYLISH2 (STY2) gene has no visible effect on gynoecium development. However, sty1-1 sty2-1 double mutant plants exhibit an enhanced sty1-1 mutant phenotype and are characterized by a further reduction in the amount of stylar and stigmatic tissues and decreased proliferation of stylar xylem. These data imply that STY1 and STY2 are partially redundant and that both genes promote style and stigma formation and influence vascular development during Arabidopsis gynoecium development. Consistently, STY1 and STY2 are expressed in the apical parts of the developing gynoecium and ectopic expression of either STY1 or STY2 driven by the CaMV 35S promoter is sufficient to transform valve cells into style cells. STY1::GUS and STY2::GUS activity is detected in many other organs as well as the gynoecium, suggesting that STY1 and STY2 may have additional functions. This is supported by the sty1-1 sty2-1 double mutants producing rosette and cauline leaves with a higher degree of serration than wild-type leaves. STY1 and STY2 are members of a small gene family, and encode proteins with a RING finger-like motif. Double mutant analyses indicate that STY1 genetically interacts with SPATULA and possibly also with CRABS CLAW.

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DNMT3A Regulates Hematopoietic Stem Cell Function Via DNA Methylation-Independent Functions

Blood ◽

10.1182/blood-2021-153759 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 24-24

Author(s):

Won Kyun Koh ◽

Hamza Celik ◽

Jacob Tao ◽

Jake Fairchild ◽

Ostap Kukhar ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Dna Methyltransferase ◽

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Ectopic Expression ◽

Wild Type ◽

Self Renewal ◽

Hematopoietic Stem ◽

Independent Functions

Abstract The balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is strictly regulated to sustain blood production throughout adult life. De novo DNA methyltransferase 3-alpha (DNMT3A) is one of the major epigenetic regulators that is essential for efficient HSC differentiation. DNMT3A mutations are prevalent in myeloid diseases that include acute myeloid leukemia (AML; ~22%) and myelodysplastic syndrome (MDS; ~10%) where they act as initiating events However, the precise molecular mechanisms of how DNMT3A regulates normal hematopoiesis and its mutations prime HSCs for leukemic formation are unclear. Although DNMT3A is described as a DNA methyltransferase enzyme, the lack of consistent correlation between changes in DNA methylation and differential gene expression in Dnmt3a-null HSCs in mouse models, and AML patients with DNMT3A mutations undermine the conventional understanding of DNMT3A's canonical role in hematopoietic cells. Hence, we hypothesized that DNMT3A may have novel functions outside of DNA methylation that regulate HSC fate decisions. To answer this question, we first ectopically expressed GFP-labeled Dnmt3a constructs (wild-type Dnmt3a, Dnmt3aE752A; complete DNA methylation dead, and Dnmt3aR832A; reduced DNA methylation target recognition) and empty vector (negative control) in Dnmt3a-null (Vav-Cre: Dnmt3afl/fl = Dnmt3a-/- in hematopoiesis) bone marrow (BM) cells. The result showed that similar to restoring wild-type Dnmt3a, ectopic expression of Dnmt3aE752A as well as Dnmt3aR832A showed a rescue effect of decreased engraftment of transduced cells in the peripheral blood as well as reduced HSC numbers in the BM. Analysis of DNA methylation by whole-genome bisulfite sequencing (WGBS) in transduced cells showed this phenotypic and functional rescue of the Dnmt3a-/- phenotype occurred in the absence of restored DNA methylation patterns. To study the importance of Dnmt3a-mediated DNA methyltransferase activity in a more physiological system, we generated knock-in mice that have one copy of either wild-type Dnmt3a, Dnmt3aE752A, or Dnmt3aR832A (CAGG-Cre-ER T2 = ER T2-Cre: Dnmt3afl/+, Dnmt3afl/E752A, and Dnmt3afl/R832A) to be compared to the Dnmt3a-null group (ER T2-Cre: Dnmt3afl/-). These mice contain one allele with loxP-flanked Dnmt3a that is deleted by tamoxifen-inducible Cre-mediated recombination and one allele of either wild-type Dnmt3a, Dnmt3aE752A, Dnmt3aR832A, or germline knockout Dnmt3anull. 5-weeks post-tamoxifen (~93% floxed allele recombination), competitive transplantation of 250 phenotypically defined test HSCs against with 2.5x10 5 congenic competitor BM cells was performed. Dnmt3a fl/R832A recipients had higher engraftment (35.6 % +/- 6.1) than Dnmt3afl/+ (28.5% +/- 7.2) and Dnmt3afl/- (10.7% +/- 2.79), while Dnmt3afl/E752A had slightly higherengraftment (12.5% +/- 3) than Dnmt3afl/-. Analysis of the BM 18 weeks post-transplant showed that Dnmt3afl/E752A and Dnmt3afl/R832A HSCs phenocopied the HSC self-renewal potential phenotype of heterozygous Dnmt3a fl/+HSCs (Fig. 1). The absolute count of donor-derived HSCs per mouse after the transplant were: ER T2-Cre control (675.7 +/- 299.3), Dnmt3afl/+ (1870 +/- 961.4), Dnmt3afl/- (3546 +/- 1019), Dnmt3afl/E752A (1130 +/- 362.7), and Dnmt3afl/R832A (1184 +/- 344.5) (mean +/- S.E.M.). While the described clonal expansion of Dnmt3a-null HSCs was observed, HSCs with one copy of full-length Dnmt3a but devoid of its methyltransferase capacity mimicked the heterozygous state rather than the homozygous loss-of-function. This is the first evidence to suggest that DNMT3A potentially regulates HSCs by non-canonical (DNA methylation independent) mechanisms. DNA methylation analysis by WGBS is ongoing to determine if Dnmt3afl/E752A and Dnmt3afl/R832A HSCs show a methylome comparable to Dnmt3a-null HSCs whilst having the functional potential of Dnmt3a-heterozygous HSCs, which will be complemented with other molecular analyses including gene expression. Our study opens new avenues for investigations into the molecular mechanisms of DNMT3A function in HSC biology, which could ultimately benefit clinical practice by identifying new therapeutic approaches for the patients with DNMT3A mutations. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Uncoupling Salicylic Acid-Dependent Cell Death and Defense-Related Responses From Disease Resistance in the Arabidopsis Mutant acd5

Genetics ◽

10.1093/genetics/156.1.341 ◽

2000 ◽

Vol 156 (1) ◽

pp. 341-350

Author(s):

Jean T Greenberg ◽

F Paul Silverman ◽

Hua Liang

Keyword(s):

Cell Death ◽

Salicylic Acid ◽

Disease Resistance ◽

Pseudomonas Syringae ◽

Higher Plants ◽

Ethylene Signaling ◽

Symptom Development ◽

Wild Type ◽

Dependent Cell ◽

Arabidopsis Mutant

Abstract Salicylic acid (SA) is required for resistance to many diseases in higher plants. SA-dependent cell death and defense-related responses have been correlated with disease resistance. The accelerated cell death 5 mutant of Arabidopsis provides additional genetic evidence that SA regulates cell death and defense-related responses. However, in acd5, these events are uncoupled from disease resistance. acd5 plants are more susceptible to Pseudomonas syringae early in development and show spontaneous SA accumulation, cell death, and defense-related markers later in development. In acd5 plants, cell death and defense-related responses are SA dependent but they do not confer disease resistance. Double mutants with acd5 and nonexpressor of PR1, in which SA signaling is partially blocked, show greatly attenuated cell death, indicating a role for NPR1 in controlling cell death. The hormone ethylene potentiates the effects of SA and is important for disease symptom development in Arabidopsis. Double mutants of acd5 and ethylene insensitive 2, in which ethylene signaling is blocked, show decreased cell death, supporting a role for ethylene in cell death control. We propose that acd5 plants mimic P. syringae-infected wild-type plants and that both SA and ethylene are normally involved in regulating cell death during some susceptible pathogen infections.

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DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Communications Biology ◽

10.1038/s42003-020-01469-0 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Vanessa Lakis ◽

◽

Rita T. Lawlor ◽

Felicity Newell ◽

Ann-Marie Patch ◽

...

Keyword(s):

Dna Methylation ◽

Neuroendocrine Tumors ◽

Methylation Profile ◽

Pancreatic Neuroendocrine Tumors ◽

Wild Type ◽

Genomic Information ◽

Chromosome 11 ◽

Dna Methylation Profile ◽

Methylation Patterns ◽

Recurrent Patterns

AbstractHere we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

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Analysis of maxillopedia Expression Pattern and Larval Cuticular Phenotype in Wild-Type and Mutant Tribolium

Genetics ◽

10.1093/genetics/155.2.721 ◽

2000 ◽

Vol 155 (2) ◽

pp. 721-731 ◽

Cited By ~ 7

Author(s):

Teresa D Shippy ◽

Jianhua Guo ◽

Susan J Brown ◽

Richard W Beeman ◽

Robin E Denell

Keyword(s):

Rna Interference ◽

Expression Pattern ◽

Tribolium Castaneum ◽

Expression Patterns ◽

Ectopic Expression ◽

Homeotic Gene ◽

Wild Type ◽

Double Stranded Rna ◽

Similar Expression ◽

Mutant Phenotypes

Abstract The Tribolium castaneum homeotic gene maxillopedia (mxp) is the ortholog of Drosophila proboscipedia (pb). Here we describe and classify available mxp alleles. Larvae lacking all mxp function die soon after hatching, exhibiting strong transformations of maxillary and labial palps to legs. Hypomorphic mxp alleles produce less severe transformations to leg. RNA interference with maxillopedia double-stranded RNA results in phenocopies of mxp mutant phenotypes ranging from partial to complete transformations. A number of gain-of-function (GOF) mxp alleles have been isolated based on transformations of adult antennae and/or legs toward palps. Finally, we have characterized the mxp expression pattern in wild-type and mutant embryos. In normal embryos, mxp is expressed in the maxillary and labial segments, whereas ectopic expression is observed in some GOF variants. Although mxp and Pb display very similar expression patterns, pb null embryos develop normally. The mxp mutant larval phenotype in Tribolium is consistent with the hypothesis that an ancestral pb-like gene had an embryonic function that was lost in the lineage leading to Drosophila.

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Ectopic Expression of the Rice Lumazine Synthase Gene Contributes to Defense Responses in Transgenic Tobacco

Phytopathology ◽

10.1094/phyto-100-6-0573 ◽

2010 ◽

Vol 100 (6) ◽

pp. 573-581 ◽

Cited By ~ 16

Author(s):

Tingquan Wu ◽

An Guo ◽

Yanying Zhao ◽

Xiaomeng Wang ◽

Ying Wang ◽

...

Keyword(s):

Jasmonic Acid ◽

Transgenic Tobacco ◽

Plant Defenses ◽

Higher Plants ◽

Synergistic Effects ◽

Ectopic Expression ◽

Defense Responses ◽

Flavin Mononucleotide ◽

Lumazine Synthase ◽

Ethylene Content

Lumazine synthase (LS) catalyzes the penultimate reaction in the multistep riboflavin biosynthesis pathway, which is involved in plant defenses. Plant defenses are often subject to synergistic effects of jasmonic acid and ethylene whereas LS is a regulator of jasmonic acid signal transduction. However, little is known about whether the enzyme contributes to defense responses. To study the role of LS in plant pathogen defenses, we generated transgenic tobacco expressing the rice (Oryza sativa) LS gene, OsLS. OsLS was cloned and found to have strong identity with its homologues in higher plants and less homology to microbial orthologues. The OsLS protein localized to chloroplasts in three OsLS-expressing transgenic tobacco (LSETT) lines characterized as enhanced in growth and defense. Compared with control plants, LSETT had higher content of both riboflavin and the cofactors flavin mononucleotide and flavin adenine dinucleotide. In LSETT, jasmonic acid and ethylene were elevated, the expression of defense-related genes was induced, levels of resistance to pathogens were enhanced, and resistance was effective to viral, bacterial, and oomycete pathogens. Extents of OsLS expression correlated with increases in flavin, jasmonic acid, and ethylene content, and correlated with increases in resistance levels, suggesting a role for OsLS in defense responses.

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Insulin Induces Heterologous Desensitization of G Protein-Coupled Receptor and Insulin-Like Growth Factor I Signaling by Downregulating β-Arrestin-1

Molecular and Cellular Biology ◽

10.1128/mcb.22.17.6272-6285.2002 ◽

2002 ◽

Vol 22 (17) ◽

pp. 6272-6285 ◽

Cited By ~ 60

Author(s):

Stéphane Dalle ◽

Takeshi Imamura ◽

David W. Rose ◽

Dorothy Sears Worrall ◽

Satoshi Ugi ◽

...

Keyword(s):

Growth Factor ◽

Map Kinase ◽

Insulin Treatment ◽

Ectopic Expression ◽

Wild Type ◽

Factor I ◽

Igf I ◽

Heterologous Desensitization ◽

Kinase Phosphorylation ◽

G Protein Coupled

ABSTRACT β-Arrestin-1 mediates agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCRs) and is also essential for GPCR mitogenic signaling. In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by β-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation. Here, we report that treatment of cells for 12 h with insulin (100 ng/ml) induces an ∼50% decrease in cellular β-arrestin-1 content due to ubiquitination of β-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in β-arrestin-1 content was blocked by inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with wortmannin and PD98059, respectively. We also found a marked decrease in the association of β-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, β-arrestin-1-downregulated cells, there was complete inhibition of lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase phosphorylation. This was associated with a decrease in β-arrestin-1 association with the β2-AR as well as a decrease in β-arrestin-1-Src and Src-β2-AR association. Ectopic expression of wild-type β-arrestin-1 in insulin-treated cells in which endogenous β-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. In conclusion, we found the following. (i) Chronic insulin treatment leads to enhanced β-arrestin-1 degradation. (ii) This downregulation of endogenous β-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type β-arrestin-1. (iii) Finally, these results describe a novel mechanism for heterologous desensitization, whereby insulin treatment can impair GPCR signaling, and highlight the importance of β-arrestin-1 as a target molecule for this desensitization mechanism.

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IC138 Defines a Subdomain at the Base of the I1 Dynein That Regulates Microtubule Sliding and Flagellar Motility

Molecular Biology of the Cell ◽

10.1091/mbc.e09-04-0277 ◽

2009 ◽

Vol 20 (13) ◽

pp. 3055-3063 ◽

Cited By ~ 43

Author(s):

Raqual Bower ◽

Kristyn VanderWaal ◽

Eileen O'Toole ◽

Laura Fox ◽

Catherine Perrone ◽

...

Keyword(s):

Double Mutant ◽

Essential Role ◽

Null Allele ◽

Flagellar Motility ◽

Wild Type ◽

Gene Encoding ◽

Radial Spoke ◽

Mutant Strains ◽

Dynein Arms ◽

Image Averaging

To understand the mechanisms that regulate the assembly and activity of flagellar dyneins, we focused on the I1 inner arm dynein (dynein f) and a null allele, bop5-2, defective in the gene encoding the IC138 phosphoprotein subunit. I1 dynein assembles in bop5-2 axonemes but lacks at least four subunits: IC138, IC97, LC7b, and flagellar-associated protein (FAP) 120—defining a new I1 subcomplex. Electron microscopy and image averaging revealed a defect at the base of the I1 dynein, in between radial spoke 1 and the outer dynein arms. Microtubule sliding velocities also are reduced. Transformation with wild-type IC138 restores assembly of the IC138 subcomplex and rescues microtubule sliding. These observations suggest that the IC138 subcomplex is required to coordinate I1 motor activity. To further test this hypothesis, we analyzed microtubule sliding in radial spoke and double mutant strains. The results reveal an essential role for the IC138 subcomplex in the regulation of I1 activity by the radial spoke/phosphorylation pathway.

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Aspergillus nidulans Protein O-Mannosyltransferases Play Roles in Cell Wall Integrity and Developmental Patterning

Eukaryotic Cell ◽

10.1128/ec.00040-09 ◽

2009 ◽

Vol 8 (10) ◽

pp. 1475-1485 ◽

Cited By ~ 33

Author(s):

Thanyanuch Kriangkripipat ◽

Michelle Momany

Keyword(s):

Cell Wall ◽

Aspergillus Nidulans ◽

Double Mutant ◽

Elevated Temperatures ◽

Cell Wall Integrity ◽

Wild Type ◽

Spatial Cues ◽

Developmental Patterning ◽

In The Wild ◽

Increased Sensitivity

ABSTRACT Protein O-mannosyltransferases (Pmts) initiate O-mannosyl glycan biosynthesis from Ser and Thr residues of target proteins. Fungal Pmts are divided into three subfamilies, Pmt1, -2, and -4. Aspergillus nidulans possesses a single representative of each Pmt subfamily, pmtA (subfamily 2), pmtB (subfamily 1), and pmtC (subfamily 4). In this work, we show that single Δpmt mutants are viable and have unique phenotypes and that the ΔpmtA ΔpmtB double mutant is the only viable double mutant. This makes A. nidulans the first fungus in which all members of individual Pmt subfamilies can be deleted without loss of viability. At elevated temperatures, all A. nidulans Δpmt mutants show cell wall-associated defects and increased sensitivity to cell wall-perturbing agents. The Δpmt mutants also show defects in developmental patterning. Germ tube emergence is early in ΔpmtA and more frequent in ΔpmtC mutants than in the wild type. In ΔpmtB mutants, intrahyphal hyphae develop. All Δpmt mutants show distinct conidiophore defects. The ΔpmtA strain has swollen vesicles and conidiogenous cells, the ΔpmtB strain has swollen conidiophore stalks, and the ΔpmtC strain has dramatically elongated conidiophore stalks. We also show that AN5660, an ortholog of Saccharomyces cerevisiae Wsc1p, is modified by PmtA and PmtC. The Δpmt phenotypes at elevated temperatures, increased sensitivity to cell wall-perturbing agents and restoration to wild-type growth with osmoticum suggest that A. nidulans Pmts modify proteins in the cell wall integrity pathway. The altered developmental patterns in Δpmt mutants suggest that A. nidulans Pmts modify proteins that serve as spatial cues.

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Retrovirus-induced interference with collagen I gene expression in Mov13 fibroblasts is maintained in the absence of DNA methylation

Molecular and Cellular Biology ◽

10.1128/mcb.11.1.47-54.1991 ◽

1991 ◽

Vol 11 (1) ◽

pp. 47-54

Author(s):

H Chan ◽

S Hartung ◽

M Breindl

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Chromatin Structure ◽

Transcriptional Activity ◽

Xenopus Laevis Oocytes ◽

Regulatory Sequences ◽

Type I ◽

Wild Type ◽

Col1a1 Gene

We have studied the role of DNA methylation in repression of the murine alpha 1 type I collagen (COL1A1) gene in Mov13 fibroblasts. In Mov13 mice, a retroviral provirus has inserted into the first intron of the COL1A1 gene and blocks its expression at the level of transcriptional initiation. We found that regulatory sequences in the COL1A1 promoter region that are involved in the tissue-specific regulation of the gene are unmethylated in collagen-expressing wild-type fibroblasts and methylated in Mov13 fibroblasts, confirming and extending earlier observations. To directly assess the role of DNA methylation in the repression of COL1A1 gene transcription, we treated Mov13 fibroblasts with the demethylating agent 5-azacytidine. This treatment resulted in a demethylation of the COL1A1 regulatory sequences but failed to activate transcription of the COL1A1 gene. Moreover, the 5-azacytidine treatment induced a transcription-competent chromatin structure in the retroviral sequences but not in the COL1A1 promoter. In DNA transfection and microinjection experiments, we found that the provirus interfered with transcriptional activity of the COL1A1 promoter in Mov13 fibroblasts but not in Xenopus laevis oocytes. In contrast, the wild-type COL1A1 promoter was transcriptionally active in Mov13 fibroblasts. These experiments showed that the COL1A1 promoter is potentially transcriptionally active in the presence of proviral sequences and that Mov13 fibroblasts contain the trans-acting factors required for efficient COL1A1 gene expression. Our results indicate that the provirus insertion in Mov13 can inactivate COL1A1 gene expression at several levels. It prevents the developmentally regulated establishment of a transcription-competent methylation pattern and chromatin structure of the COL1A1 domain and, in the absence of DNA methylation, appears to suppress the COL1A1 promoter in a cell-specific manner, presumably by assuming a dominant chromatin structure that may be incompatible with transcriptional activity of flanking cellular sequences.

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