Juvenile hormones and the genetic interaction between the transcription factors <i>Krüppel ... more Juvenile hormones and the genetic interaction between the transcription factors <i>Krüppel homologue 1</i> (<i>Kr-h1</i>) and <i>Broad</i> (<i>Br</i>) regulate the transformation of insects from immature to adult forms in both types of metamorphosis (holometaboly with a pupal stage versus hemimetaboly with no pupal stage); however, knowledge about the exact instar in which this occurs is limited. Using the hemimetabolous cricket <i>Gryllus bimaculatus</i> (<i>Gb</i>), we demonstrate that a genetic interaction occurs among <i>Gb</i>′<i>Kr-h1</i>, <i>Gb</i>′<i>Br</i> and the adult-specifier transcription factor <i>Gb</i>′<i>E93</i> from the sixth to final (eighth) nymphal instar. <i>Gb</i>′<i>Kr-h1</i> and <i>Gb</i>′<i>Br</i> mRNAs were strongly expressed in the abdominal tissues of sixth instar nymphs, with precocious adult moults being induced by <i>Gb</i>′<i>Kr-h1</i> or <i>Gb</i>′<i>Br</i> knockdown in the sixth instar. The depletion of <i>Gb</i>′<i>Kr-h1</i> or <i>Gb</i>′<i>Br</i> upregulates <i>Gb</i>′<i>E93</i> in the sixth instar. By contrast, <i>Gb</i>′<i>E93</i> knockdown at the sixth instar prevents nymphs transitioning to adults, instead producing supernumerary nymphs. <i>Gb</i>′<i>E93</i> also represses <i>Gb</i>′<i>Kr-h1</i> and <i>Gb</i>′<i>Br</i> expression in the penultimate nymphal instar, demonstrating its important role in adult differentiation. Our results suggest that the regulatory mechanisms underlying the pupal transition in holometabolous insects are evolutionarily conserved in hemimetabolous <i>G</i>. <i>bimaculatus</i>, with the penultimate and final nymphal periods being equivalent to the pupal stage.This article is part of the theme issue 'The evolution of complete metamorphosis'.
In contrast to higher vertebrates, orthopteran nymphs have remarkable regenerative capacity for r... more In contrast to higher vertebrates, orthopteran nymphs have remarkable regenerative capacity for regrowing complex morphological structures and organs. In this review, we summarize the molecular basis of tissue regeneration in the cricket Gryllus bimaculatus. In this species, the lost part of a leg can be regenerated epimorphically from blastema cells, a population of dedifferentiated proliferating cells. Blastema cell proliferation is regulated by JAK/STAT and Salvador/Warts/Hippo signaling pathways. The positional information for leg regrowth, which includes the recognition of amputated position and proper regeneration, is maintained by Dachsous/Fat signaling. The regrowth of lost leg segments is reconstructed through the expressions of genes in the hedgehog, wingless, decapentaplegic, and Egf signaling pathways and epigenetic modifiers E(z) and Utx. The insights obtained reveal the high level of conservation between insects and vertebrates, suggesting that Gryllus may be a suitable model for human regenerative medicine studies.
Retinol-binding protein (RBP), a plasma protein with a molecular weight of 21,000 daltons, binds ... more Retinol-binding protein (RBP), a plasma protein with a molecular weight of 21,000 daltons, binds to retinol with a 1:1 molar ratio and transports it to the peripheral tissues. Familial hypo-retinol-binding proteinemia (hypo-RBPnemia) was detected in a 2-year-old girl who developed keratomalacia, and in her mother and sister. They persistently showed half the normal levels of RBP and retinol. Restriction fragments of leukocyte DNA, created by digestion with BamHI, EcoRI and PstI when human RBP complementary DNA was used as a probe, showed the same patterns in both the affected and unaffected family members. These results indicate that familial hypo-RBPnemia could be attributed to such minor changes as point mutations, rather than large deletion or insertion in the RBP gene.
Crucial points of in situ hybridization methods were pointed out for study on the kidney diseases... more Crucial points of in situ hybridization methods were pointed out for study on the kidney diseases at molecular level. As examples of in situ hybridization study on kidney, we introduced two cases: 1) expression of the hepatocyte growth factor gene during renal regeneration after unilateral nephrectomy, and 2) induction of the metallothionein gene expression by ischemic acute renal failure. We proposed an idea to establish a probe bank for the in situ hybridization study.
Vertebrate limb morphogenesis has been investigated as a model system of pattern formation. Recen... more Vertebrate limb morphogenesis has been investigated as a model system of pattern formation. Recent results suggest that peptide growth factors are involved in the limb morphogenesis. Members of the fibroblast growth factor family stimulate proliferation of the limb mesenchymal cells, while members of the transforming growth factor (TGF)-β family, in contrast, inhibit the proliferation. The antagonistic effect between the two families is probably essential for establishment of both anteroposterior and proximodistal axes. The Wnt and TGF-β families may be related to morphogenesis of the dorsoventral axis. The three families are also involved in chondrogenesis, osteogenesis, and feather formation. In this review, possible roles of such growth factors and their receptors in morphogenesis of the limb are discussed.
The sequential transphosphorylation from autophosphorylated nitrate-sensing protein (NarX) to the... more The sequential transphosphorylation from autophosphorylated nitrate-sensing protein (NarX) to the transcriptional regulator protein (NarL), both operating in signal transduction to control the expression of the respiratory nitrate reductase (nar) operon in E. coli, was demonstrated with an in vitro reconstructed system to function similarly to other bacterial two-component regulatory systems. Over-expression system established by means of the pT7 promoter/polymerase provided both NarX and NarL proteins to reconstruct the in vitro transphosphorylation system. The phosphorylated NarL was detected, and the unstable phosphorylated group was directly assigned to acyl phosphate in the in vitro system by 31P-NMR spectroscopy.
Caveolins, components of the uncoated invaginations of plasma membrane, regulate signal transduct... more Caveolins, components of the uncoated invaginations of plasma membrane, regulate signal transduction and vesicular trafflicking. Loss of caveolin-3, resulting from dominant negative mutations of caveolin-3 causes autosomal dominant limb-girdle muscular dystrophy (LGMD) 1C and autosomal dominant rippling muscle disease (AD-RMD). Myostatin, a member of the muscle-specific transforming growth factor (TGF)-beta superfamily, negatively regulates skeletal muscle volume. Herein we review caveolin-3 suppressing of activation of type I myostatin receptor, thereby inhibiting subsequent intracellular signaling. In addition, a mouse model of LGMD1C has shown atrophic myopathy with enhanced myostatin signaling. Myostatin inhibition ameliorates muscular phenotype in the model mouse, accompanied by normalized myostatin signaling. Enhanced myostatin signaling by caveolin-3 mutation in human may contribute to the pathogenesis of LGMD1C. Therefore, myostatin inhibition therapy may be a promising treatment for patients with LGMD1C. More recent studies concerning regulation of TGF-beta superfamily signaling by caveolins have provided new insights into the pathogenesis of several human diseases.
Crickets are currently in focus as a possible source of animal protein for human consumption as a... more Crickets are currently in focus as a possible source of animal protein for human consumption as an alternative to protein from vertebrate livestock. This practice could ease some of the challenges both of a worldwide growing population and of environmental issues. The twospotted Mediterranean field cricket Gryllus bimaculatus has traditionally been consumed by humans in different parts of the world. Not only is this considered generally safe for human consumption, several studies also suggest that introducing crickets into one's diet may confer multiple health benefits. Moreover, G. bimaculatus has been widely used as a laboratory research model for decades in multiple scientific fields including evolution, developmental biology, neurobiology, and regeneration. Here we report the sequencing, assembly and annotation of the G. bimaculatus genome, and the annotation of the genome of the Hawaiian cricket Laupala kohalensis. The comparison of these two cricket genomes with those of 14 additional insects supports the hypothesis that a relatively small ancestral insect genome expanded to large sizes in many hemimetabolous lineages due to transposable element activity. Based on the ratio of observed versus expected CpG sites (CpGo/e), we find higher conservation and stronger purifying selection of typically methylated genes than of non-methylated genes. Finally, our gene family expansion analysis reveals an expansion of the pickpocket class V gene family in the lineage leading to crickets, which we speculate might play a relevant role in cricket courtship behavior, including their characteristic chirping. .
When a mouse zone of polarizing activity (ZPA) at the posterior margin of the limb bud was grafte... more When a mouse zone of polarizing activity (ZPA) at the posterior margin of the limb bud was grafted at the anterior margin of the chick limb bud, we found that expression of the chick homeobox genes, Chox-4.7 and -4.8, was induced prior to the formation of chick extra digits. The induction was observed in the restricted domain close to both grafted mouse ZPA and the chick apical ectodermal ridge (AER). When the posterior half of the AER was removed, the normal expression was diminished in the posterodistal region. Thus, it is likely that at least two distinct factors, one from the ZPA and the other from the AER, provide positional information to induce cooperatively the sequential expression of the Chox-4 genes.
Activin is known to induce axial mesoderm during early development in Xenopus embryo. Activin rec... more Activin is known to induce axial mesoderm during early development in Xenopus embryo. Activin receptor was recently identified to be a member of transmembrane serine/threonine kinase family. We have studied the role of activin-mediated signaling in the limb morphogenesis by identifying the target cells. We isolated cDNAs encoding chicken activin receptors, cARIIA and cARIIB, and examined their expression patterns during chick embryogenesis. The cARIIA gene is expressed in the apical ectoderm of the limb bud at stage 20-21, whereas the cARIIB gene is expressed uniformly in the limb mesenchyme. Expression of the cARIIA gene is confined to dorsal and ventral mesenchyme at stage 23, and later confined to precartilaginous cells. Transcripts of the cARIIA gene are found in developing neuroepithelium of spinal cord, brain and eye, surface ectoderm differentiating to epidermis, and myoblasts differentiating to muscle. The IIB receptor gene is highly expressed in the developing brain. These results suggest that the activins and their receptors are implicated in the limb development, especially, in differentiation of muscle, skin and bone.
It is demonstrated that the change in the spin label ESR spectrum induced by shear flow reflects ... more It is demonstrated that the change in the spin label ESR spectrum induced by shear flow reflects the whole cell deformation as a function of the cell surface area-to-volume ratio (s/v), the morphology and intracellular viscosity. Since the effect of the change in the membrane mechanical property on the ESR spectrum has been described previously, the spin label ESR spectrum is now shown to contain full information concerning the whole cell deformability which is determined by the major intrinsic and extrinsic properties of the red blood cells. The result of microphotographic observations shows also that the cells in the flow are elongated and aligned approximately along the flow direction to an increasing extent as the cells flow near the surface of the flat channel walls. Thus, the entire observation confirms the view that the ESR spectral difference-shear rate profile is closely related to the elongation ratio shear rate characteristics obtained by other (optical) methods.
The Ca2"-induced loss of deformability in human erythrocytes and the recovery of the lost deforma... more The Ca2"-induced loss of deformability in human erythrocytes and the recovery of the lost deformability by stomatocytogenic reagents were investigated by means of a new flow electron paramagnetic resonance (EPR) spin label method, which provides information on deformation and orientation characteristics of spin labeled erythrocytes in shear flow. The Ca2"-induced loss of deformability is attributed mainly to the increase in intracellular viscosity resulting from efflux of intracellular potassium ions and water (Gardos effect). Partial recovery of the lost deformability is demonstrated in the presence of stomatocytogenic reagents, such as chlorpromazine, trifluoperazine, W-7, and calmidazolium (R2457 1). The recovery can not be explained solely by suppression of the Gardos effect due to the reagents. Incorporation of an optimal amount of the reagents into the membrane appears to compensate for the membrane modification due to Ca2+ ions to restore a part of the lost deformability.
Expression patterns of three fibroblast growth factor receptor genes, FGFR1 (cek1), FGFR2 (cek3) ... more Expression patterns of three fibroblast growth factor receptor genes, FGFR1 (cek1), FGFR2 (cek3) and FGFR3 (cek2), were observed in limb and feather morphogenesis. Expression of FGFR1 was observed in the mesoderm of limb bud, in the mesenchyme just underneath the feather placode, and then in the anterior mesenchyme of the feather bud. While expression of FGFR2 was observed in both surface ectoderm and mesenchymal aggregates corresponding to the future bones of the limb, the mesenchyme between the feather placode, and surface ectoderm of feather buds. Expression of FGFR3 was observed rather ubiquitously over mesoderm of limb and feather buds. Differential expression of these FGF receptor genes suggested that differential roles of these receptors in epithelia-mesenchymal interactions of limb and feather morphogenesis.
Juvenile hormones and the genetic interaction between the transcription factors <i>Krüppel ... more Juvenile hormones and the genetic interaction between the transcription factors <i>Krüppel homologue 1</i> (<i>Kr-h1</i>) and <i>Broad</i> (<i>Br</i>) regulate the transformation of insects from immature to adult forms in both types of metamorphosis (holometaboly with a pupal stage versus hemimetaboly with no pupal stage); however, knowledge about the exact instar in which this occurs is limited. Using the hemimetabolous cricket <i>Gryllus bimaculatus</i> (<i>Gb</i>), we demonstrate that a genetic interaction occurs among <i>Gb</i>′<i>Kr-h1</i>, <i>Gb</i>′<i>Br</i> and the adult-specifier transcription factor <i>Gb</i>′<i>E93</i> from the sixth to final (eighth) nymphal instar. <i>Gb</i>′<i>Kr-h1</i> and <i>Gb</i>′<i>Br</i> mRNAs were strongly expressed in the abdominal tissues of sixth instar nymphs, with precocious adult moults being induced by <i>Gb</i>′<i>Kr-h1</i> or <i>Gb</i>′<i>Br</i> knockdown in the sixth instar. The depletion of <i>Gb</i>′<i>Kr-h1</i> or <i>Gb</i>′<i>Br</i> upregulates <i>Gb</i>′<i>E93</i> in the sixth instar. By contrast, <i>Gb</i>′<i>E93</i> knockdown at the sixth instar prevents nymphs transitioning to adults, instead producing supernumerary nymphs. <i>Gb</i>′<i>E93</i> also represses <i>Gb</i>′<i>Kr-h1</i> and <i>Gb</i>′<i>Br</i> expression in the penultimate nymphal instar, demonstrating its important role in adult differentiation. Our results suggest that the regulatory mechanisms underlying the pupal transition in holometabolous insects are evolutionarily conserved in hemimetabolous <i>G</i>. <i>bimaculatus</i>, with the penultimate and final nymphal periods being equivalent to the pupal stage.This article is part of the theme issue 'The evolution of complete metamorphosis'.
In contrast to higher vertebrates, orthopteran nymphs have remarkable regenerative capacity for r... more In contrast to higher vertebrates, orthopteran nymphs have remarkable regenerative capacity for regrowing complex morphological structures and organs. In this review, we summarize the molecular basis of tissue regeneration in the cricket Gryllus bimaculatus. In this species, the lost part of a leg can be regenerated epimorphically from blastema cells, a population of dedifferentiated proliferating cells. Blastema cell proliferation is regulated by JAK/STAT and Salvador/Warts/Hippo signaling pathways. The positional information for leg regrowth, which includes the recognition of amputated position and proper regeneration, is maintained by Dachsous/Fat signaling. The regrowth of lost leg segments is reconstructed through the expressions of genes in the hedgehog, wingless, decapentaplegic, and Egf signaling pathways and epigenetic modifiers E(z) and Utx. The insights obtained reveal the high level of conservation between insects and vertebrates, suggesting that Gryllus may be a suitable model for human regenerative medicine studies.
Retinol-binding protein (RBP), a plasma protein with a molecular weight of 21,000 daltons, binds ... more Retinol-binding protein (RBP), a plasma protein with a molecular weight of 21,000 daltons, binds to retinol with a 1:1 molar ratio and transports it to the peripheral tissues. Familial hypo-retinol-binding proteinemia (hypo-RBPnemia) was detected in a 2-year-old girl who developed keratomalacia, and in her mother and sister. They persistently showed half the normal levels of RBP and retinol. Restriction fragments of leukocyte DNA, created by digestion with BamHI, EcoRI and PstI when human RBP complementary DNA was used as a probe, showed the same patterns in both the affected and unaffected family members. These results indicate that familial hypo-RBPnemia could be attributed to such minor changes as point mutations, rather than large deletion or insertion in the RBP gene.
Crucial points of in situ hybridization methods were pointed out for study on the kidney diseases... more Crucial points of in situ hybridization methods were pointed out for study on the kidney diseases at molecular level. As examples of in situ hybridization study on kidney, we introduced two cases: 1) expression of the hepatocyte growth factor gene during renal regeneration after unilateral nephrectomy, and 2) induction of the metallothionein gene expression by ischemic acute renal failure. We proposed an idea to establish a probe bank for the in situ hybridization study.
Vertebrate limb morphogenesis has been investigated as a model system of pattern formation. Recen... more Vertebrate limb morphogenesis has been investigated as a model system of pattern formation. Recent results suggest that peptide growth factors are involved in the limb morphogenesis. Members of the fibroblast growth factor family stimulate proliferation of the limb mesenchymal cells, while members of the transforming growth factor (TGF)-β family, in contrast, inhibit the proliferation. The antagonistic effect between the two families is probably essential for establishment of both anteroposterior and proximodistal axes. The Wnt and TGF-β families may be related to morphogenesis of the dorsoventral axis. The three families are also involved in chondrogenesis, osteogenesis, and feather formation. In this review, possible roles of such growth factors and their receptors in morphogenesis of the limb are discussed.
The sequential transphosphorylation from autophosphorylated nitrate-sensing protein (NarX) to the... more The sequential transphosphorylation from autophosphorylated nitrate-sensing protein (NarX) to the transcriptional regulator protein (NarL), both operating in signal transduction to control the expression of the respiratory nitrate reductase (nar) operon in E. coli, was demonstrated with an in vitro reconstructed system to function similarly to other bacterial two-component regulatory systems. Over-expression system established by means of the pT7 promoter/polymerase provided both NarX and NarL proteins to reconstruct the in vitro transphosphorylation system. The phosphorylated NarL was detected, and the unstable phosphorylated group was directly assigned to acyl phosphate in the in vitro system by 31P-NMR spectroscopy.
Caveolins, components of the uncoated invaginations of plasma membrane, regulate signal transduct... more Caveolins, components of the uncoated invaginations of plasma membrane, regulate signal transduction and vesicular trafflicking. Loss of caveolin-3, resulting from dominant negative mutations of caveolin-3 causes autosomal dominant limb-girdle muscular dystrophy (LGMD) 1C and autosomal dominant rippling muscle disease (AD-RMD). Myostatin, a member of the muscle-specific transforming growth factor (TGF)-beta superfamily, negatively regulates skeletal muscle volume. Herein we review caveolin-3 suppressing of activation of type I myostatin receptor, thereby inhibiting subsequent intracellular signaling. In addition, a mouse model of LGMD1C has shown atrophic myopathy with enhanced myostatin signaling. Myostatin inhibition ameliorates muscular phenotype in the model mouse, accompanied by normalized myostatin signaling. Enhanced myostatin signaling by caveolin-3 mutation in human may contribute to the pathogenesis of LGMD1C. Therefore, myostatin inhibition therapy may be a promising treatment for patients with LGMD1C. More recent studies concerning regulation of TGF-beta superfamily signaling by caveolins have provided new insights into the pathogenesis of several human diseases.
Crickets are currently in focus as a possible source of animal protein for human consumption as a... more Crickets are currently in focus as a possible source of animal protein for human consumption as an alternative to protein from vertebrate livestock. This practice could ease some of the challenges both of a worldwide growing population and of environmental issues. The twospotted Mediterranean field cricket Gryllus bimaculatus has traditionally been consumed by humans in different parts of the world. Not only is this considered generally safe for human consumption, several studies also suggest that introducing crickets into one's diet may confer multiple health benefits. Moreover, G. bimaculatus has been widely used as a laboratory research model for decades in multiple scientific fields including evolution, developmental biology, neurobiology, and regeneration. Here we report the sequencing, assembly and annotation of the G. bimaculatus genome, and the annotation of the genome of the Hawaiian cricket Laupala kohalensis. The comparison of these two cricket genomes with those of 14 additional insects supports the hypothesis that a relatively small ancestral insect genome expanded to large sizes in many hemimetabolous lineages due to transposable element activity. Based on the ratio of observed versus expected CpG sites (CpGo/e), we find higher conservation and stronger purifying selection of typically methylated genes than of non-methylated genes. Finally, our gene family expansion analysis reveals an expansion of the pickpocket class V gene family in the lineage leading to crickets, which we speculate might play a relevant role in cricket courtship behavior, including their characteristic chirping. .
When a mouse zone of polarizing activity (ZPA) at the posterior margin of the limb bud was grafte... more When a mouse zone of polarizing activity (ZPA) at the posterior margin of the limb bud was grafted at the anterior margin of the chick limb bud, we found that expression of the chick homeobox genes, Chox-4.7 and -4.8, was induced prior to the formation of chick extra digits. The induction was observed in the restricted domain close to both grafted mouse ZPA and the chick apical ectodermal ridge (AER). When the posterior half of the AER was removed, the normal expression was diminished in the posterodistal region. Thus, it is likely that at least two distinct factors, one from the ZPA and the other from the AER, provide positional information to induce cooperatively the sequential expression of the Chox-4 genes.
Activin is known to induce axial mesoderm during early development in Xenopus embryo. Activin rec... more Activin is known to induce axial mesoderm during early development in Xenopus embryo. Activin receptor was recently identified to be a member of transmembrane serine/threonine kinase family. We have studied the role of activin-mediated signaling in the limb morphogenesis by identifying the target cells. We isolated cDNAs encoding chicken activin receptors, cARIIA and cARIIB, and examined their expression patterns during chick embryogenesis. The cARIIA gene is expressed in the apical ectoderm of the limb bud at stage 20-21, whereas the cARIIB gene is expressed uniformly in the limb mesenchyme. Expression of the cARIIA gene is confined to dorsal and ventral mesenchyme at stage 23, and later confined to precartilaginous cells. Transcripts of the cARIIA gene are found in developing neuroepithelium of spinal cord, brain and eye, surface ectoderm differentiating to epidermis, and myoblasts differentiating to muscle. The IIB receptor gene is highly expressed in the developing brain. These results suggest that the activins and their receptors are implicated in the limb development, especially, in differentiation of muscle, skin and bone.
It is demonstrated that the change in the spin label ESR spectrum induced by shear flow reflects ... more It is demonstrated that the change in the spin label ESR spectrum induced by shear flow reflects the whole cell deformation as a function of the cell surface area-to-volume ratio (s/v), the morphology and intracellular viscosity. Since the effect of the change in the membrane mechanical property on the ESR spectrum has been described previously, the spin label ESR spectrum is now shown to contain full information concerning the whole cell deformability which is determined by the major intrinsic and extrinsic properties of the red blood cells. The result of microphotographic observations shows also that the cells in the flow are elongated and aligned approximately along the flow direction to an increasing extent as the cells flow near the surface of the flat channel walls. Thus, the entire observation confirms the view that the ESR spectral difference-shear rate profile is closely related to the elongation ratio shear rate characteristics obtained by other (optical) methods.
The Ca2"-induced loss of deformability in human erythrocytes and the recovery of the lost deforma... more The Ca2"-induced loss of deformability in human erythrocytes and the recovery of the lost deformability by stomatocytogenic reagents were investigated by means of a new flow electron paramagnetic resonance (EPR) spin label method, which provides information on deformation and orientation characteristics of spin labeled erythrocytes in shear flow. The Ca2"-induced loss of deformability is attributed mainly to the increase in intracellular viscosity resulting from efflux of intracellular potassium ions and water (Gardos effect). Partial recovery of the lost deformability is demonstrated in the presence of stomatocytogenic reagents, such as chlorpromazine, trifluoperazine, W-7, and calmidazolium (R2457 1). The recovery can not be explained solely by suppression of the Gardos effect due to the reagents. Incorporation of an optimal amount of the reagents into the membrane appears to compensate for the membrane modification due to Ca2+ ions to restore a part of the lost deformability.
Expression patterns of three fibroblast growth factor receptor genes, FGFR1 (cek1), FGFR2 (cek3) ... more Expression patterns of three fibroblast growth factor receptor genes, FGFR1 (cek1), FGFR2 (cek3) and FGFR3 (cek2), were observed in limb and feather morphogenesis. Expression of FGFR1 was observed in the mesoderm of limb bud, in the mesenchyme just underneath the feather placode, and then in the anterior mesenchyme of the feather bud. While expression of FGFR2 was observed in both surface ectoderm and mesenchymal aggregates corresponding to the future bones of the limb, the mesenchyme between the feather placode, and surface ectoderm of feather buds. Expression of FGFR3 was observed rather ubiquitously over mesoderm of limb and feather buds. Differential expression of these FGF receptor genes suggested that differential roles of these receptors in epithelia-mesenchymal interactions of limb and feather morphogenesis.
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Papers by Sumihare Noji