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At least 1,369 records · Page 76Linked to original sources
PubMed2005

Postnatal stem cell survival: does the niche, a rare harbor where to resist the ebb tide of differentiation, also provide lineage-specific instructions?

Postnatal stem cells regulate the homeostasis of the majority of our tissues. They continuously generate new progenitors and mature, functional cells to replace old cells, which cannot assume the tissue function anymore and are eliminated. Blood, skin, gut mucosa, muscle, cartilage, nerves, cornea, retina, liver, and many other structures are regulated by stem cells. As a result of their ability to produce large numbers of functionally mature cells, postnatal stem cells represent a promising tool for regenerative therapy. Indeed, unmanipulated stem cells or their progeny amplified in vitro are already used in some clinical applications to restore the function of injured or genetically deficient tissues. However, despite our cumulating understanding concerning postnatal stem cells, many aspects of their functionality remain unclear. For instance, in most tissues, we cannot reliably define the phenotype of the postnatal stem cells sustaining its survival. We do not know to which extent the environment surrounding the stem cell-the niche-which is a key actor insuring stem cell self-maintenance, is also implicated in the maintenance of stem cell lineage specificity. Moreover, we have to clarify whether postnatal stem cells are capable of undertaking "transdifferentiation", that is, the conversion of one cell type into another under physiological conditions. Answering these questions should help us to draw a more accurate picture of postnatal stem cell biology and should lead to the design of safe, effective therapies.

Cell Differentiation↗
PubMed2005

Basic progress and future therapeutic perspectives of relaxin in ischemic heart disease.

Relaxin has been validated as a cardiotropic hormone, being produced by the heart and acting on specific heart receptors. Evidence is accumulating that it could hamper the pathophysiologic mechanisms of ischemic heart disease. Time is ripe to study relaxin as a cardiotropic drug, as recombinant human relaxin (hrRLX) is now available and previous clinical trials have shown a virtual lack of toxicity and adverse side effects, even at high doses. Our recent observations suggest that relaxin, besides being a preventative agent, may also be effective in the treatment of acute myocardial infarction and may be an adjuvant for precursor cell grafting to repair postinfarct myocardium. In a swine model of myocardial infarction currently used to test cardiotropic drugs due to its similarities with human ischemic heart disease, hrRLX, given at reperfusion upon 30 min of ischemia, markedly reduced serum and tissue markers of myocardial injury, cardiomyocyte apoptosis and leukocyte recruitment, resulting in overall improvement in cardiac performance compared with the controls. In in vitro mixed cultures of mouse skeletal myoblasts and adult rat cardiomyocytes, relaxin increased gap junction formation and potentiated gap junction-mediated intercellular exchanges and signaling between the coupled cells. In view of the therapeutic use of myoblast grafting for cardiac repair, relaxin could hence favor the electromechanical coupling of grafted myoblasts with the resident cardiomyocytes and facilitate their transdifferentiation towards a cardiac phenotype. Relaxin, therefore, shows promising therapeutic potential in cardiology and cardiac surgery.

Animals↗
PubMed2005

Relaxin favors the morphofunctional integration between skeletal myoblasts and adult cardiomyocytes in coculture.

We have investigated the interaction between mouse skeletal myoblasts and rat cardiomyocytes in coculture and the influence of relaxin. Connexin43 expression, Lucifer yellow microinjection, Ca2+ propagation, and electrophysiological analysis have shown that myoblasts and cardiomyocytes are coupled by functional gap junctions. Cardiomyocytes and relaxin upregulated connexin43 expression and gap junctional communication in myoblasts. Relaxin also increased transjunctional current between myoblasts and between myoblasts and cardiomyocytes. In conclusion, relaxin potentiates the intercellular coupling, upregulating the transcellular exchange of regulatory molecules between myoblasts and cardiomyocytes, including Ca2+. This could favor the transdifferentiation of myoblasts toward a cardiac phenotype.

Aging↗
PubMed2005

Clonal multilineage differentiation of murine common pluripotent stem cells isolated from skeletal muscle and adipose stromal cells.

Pluripotent stem cells (PSCs) with transdifferentiation capacity may provide useful therapeutic modalities in the areas of cellular restoration and regenerative medicine. The utility of PSCs depends on their ability to respond to different stimuli and to adapt to tissue-specific differentiation conditions. Given that a number of cells possessing characteristics of PSCs have been identified and isolated from several adult murine tissues, we hypothesized that a common PSC may exist in multiple murine tissues and that these cells may either reside permanently in specific sites or continue to circulate and colonize tissues as needed. Previous data from our laboratory suggest that PSCs exhibiting an immunophenotype of CD45(-)Sca-1(+)c-kit(-)Thy-1(+) can be isolated from multiple murine tissues and may represent putative common PSCs (CoPSCs). To investigate whether the multiple tissue differentiation potential observed with these cells resulted from the presence of different tissue-restricted progenitors within CD45(-)Sca-1(+)c-kit(-)Thy-1(+) cells or was the product of clonal differentiation of CoPSCs, clonality studies were performed. Single skeletal muscle (SM)-derived CoPSCs were expanded for 10 days, and progeny cells were split into three culture conditions designed to stimulate myogenic, adipogenic, and neurogenic differentiation. Analysis of 600 clones indicated that 2.16%, 0.83%, and 0.33% of the total number of plated single cells were capable of unipotent, bipotent, and tripotent differentiation, respectively, into combinations of myocytes, adipocytes, and neuronal cells. Given that SM-derived CoPSCs represent 4.78% of the total cells analyzed, tripotent CoPSCs made up 0.016% of the total muscle cells. Similar results were obtained in clonal analyses using adipose stromal cell (ASC)-derived CoPSCs, suggesting that both SM- and ASC-derived CoPSCs may be phenotypically and functionally identical. Taken together, these data demonstrate that a common PSC can be identified in different murine tissues and suggest that a small fraction of these cells are capable of clonal differentiation into multiple cell types.

Adipocytes↗
PubMed2006

Transcriptional profiling and functional genomics reveal a role for AHR transcription factor in nephrogenesis.

Transcriptional profiling and functional genomics experiments using E11.5 metanephros organ cultures from Ahr(-/-) and Ahr(+/+) have shown that aryl hydrocarbon receptor (AHR) transcription factor is involved in the regulation of mesenchymal-to-epithelial transition (MET) during nephrogenesis. This response is mediated by alterations in the post-transcriptional control of Wilms' tumor suppressor (Wt1) gene and Wt1 splicing. In this article, biologically relevant gene predictor sets of the nephrogenic response were calculated for target genes of interest. The predictability of the gene set for each target was quantified by the coefficient of determination which provided a good criterion for identification of predictor sets that define the complex gene-gene interactions co-regulated by Ahr and Wt1. A subset of the signature genes was found to be co-regulated by Ahr and Wt1 and was responsible for shifts in renal cell transdifferentiation.

Animals↗
PubMed2006

Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells.

Brain damage around birth may cause lifelong neurodevelopmental deficits. We examined the therapeutic potential of human umbilical cord blood-derived mononuclear cells containing multipotent stem cells to facilitate motor recovery after cerebral hypoxic-ischemic damage in neonatal rats. Left carotid artery ligation followed by 8% O(2) inhalation for 80 min was performed on postnatal d 7, succeeded by intraperitoneal transplantation of human umbilical cord blood-derived mononuclear cells on postnatal d 8 in a sham-controlled design. Histologic and immunohistochemical analysis on postnatal d 21 revealed that neonates developed severe cerebral damage after the hypoxic-ischemic insult. These animals also suffered from contralateral spastic paresis, as evidenced by their locomotor behavior. After transplantation of human umbilical cord blood-derived mononuclear cells, spastic paresis was largely alleviated, resulting in a normal walking behavior. This "therapeutic" effect was accompanied by the fact that mononuclear cells had entered the brain and were incorporated around the lesion without obvious signs of transdifferentiation. This study demonstrates that intraperitoneal transplantation of human umbilical cord blood-derived mononuclear cells in a rat model of perinatal brain damage leads to both incorporation of these cells in the lesioned brain area and to an alleviation of the neurologic effects of cerebral palsy as assessed by footprint and walking pattern analysis.

Animals↗
PubMed2004

Multifunctional cells in human pituitary adenomas: implications for paradoxical secretion and tumorigenesis.

Pituitary adenomas are very common in humans. They are of monoclonal origin, very heterogeneous, and produce frequently paradoxical secretion. The normal anterior pituitary (AP) contains some unorthodox multifunctional cells able to store more than one AP hormone (polyhormonal) and/or to express multiple hypothalamic-releasing hormone receptors (multiresponsive). Multifunctional AP cells seem to be involved in plasticity processes such as transdifferentiation or paradoxical secretion. Here, we have characterized the single-cell phenotypes of 15 human pituitary tumors, including prolactinomas, nonfunctioning adenomas, and adenomas from multiple endocrine neoplasia type I (MEN-I) and pituitary Cushing's disease patients. Individual tumor cells were typed according to expression of AP hormones and hypothalamic-releasing hormone receptors by combination of calcium imaging and multiple sequential immunocytochemistry in the same cells. We found a large heterogeneity among the different tumors. In eight of the 15 tumors studied, more than 80% of the cells presented a multifunctional phenotype. This may explain the occurrence of paradoxical secretion. In addition, our results suggest that human pituitary adenomas might derive from multifunctional cells. This is consistent with the existence of a link between pituitary plasticity and tumorigenesis.

Adenoma↗
PubMed1996

Usefulness of 123I-metaiodobenzylguanidine (MIBG) scintiscan in the diagnosis of juxta-adrenal schwannoma.

The adrenal scintiscan with 123I-metaiodobenzylguanidine (MIBG), a reliable morphofunctional technique to evaluate catecholamine turnover in adrenal tumors, can be a useful method to investigate adrenal incidentalomas with arterial hypertension. A male patient, 44 yr old with diabetes, unstable arterial hypertension, and sudden paroxysms of tachycardia is described. The presence of a disomogeneous right juxta-adrenal neoplasm with calcifications was evidenced with ultrasound tomography and confirmed by computerized tomography (CT) scan. Adrenal 123I-MIBG scintiscan revealed a unilateral uptake at level of the right juxta-adrenal region, sized similarly to the neoplasm previously evidence by CT scan. Histological findings of the surgically removed neoplasm were consistent with an ancient schwannoma. Apart from pheochromocytomas, the MIBG uptake is commonly reported in neuroblastomas. In neuroblastoma, a bidirectional process of transdifferentiation has been previously reported in vitro between two coexistent cells: cells with specific uptake system for norepinephrine, with 123I-MIBG uptake capability, and cells oriented toward schwann/melanocytic line. The evidence of in vivo MIBG uptake in our schwannoma may be caused by the same possible phenotypic interconversion of above mentioned cell types. In conclusion, the presence of adrenal tumors with MIBG uptake capability, apart from pheochromocytomas, neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, must be considered in the diagnosis of adrenal tumors.

3-Iodobenzylguanidine↗
PubMed2006

Activin A decreases glucagon and arx gene expression in alpha-cell lines.

Activin A is a potent growth and differentiation factor involved in development, differentiation, and physiological functions of the endocrine pancreas; it increases insulin and pax4 gene expression in beta-cells and can induce transdifferentiation of the exocrine acinar cell line AR42J into insulin-producing cells. We show here that Activin A decreases glucagon gene expression in the alpha-cell lines InR1G9 and alphaTC1 in a dose- and time-dependent manner and that the effect is blocked by Follistatin. This effect is also observed in adult human islets. Glucagon gene expression is inhibited at the transcriptional level by the Smad signaling pathway through the G3 DNA control element. Furthermore, Activin A decreases cell proliferation of InR1G9 and alphaTC1 cells as well as cyclin D2 and arx gene expression, whose protein product Arx has been shown to be critical for alpha-cell differentiation. Overexpression of Arx in Activin A-treated InR1G9 cells does not prevent the decrease in glucagon gene expression but corrects the inhibition of cell proliferation, indicating that Arx mediates the Activin A effects on the cell cycle. We conclude that Activin A has opposite effects on alpha-cells compared with beta-cells, a finding that may have relevance during pancreatic endocrine lineage specification and physiological function of the adult islets.

Activins↗
PubMed2003

Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6.

The transcription factors Pax2 and Pax6 are co-expressed in the entire optic vesicle (OV) prior and concomitant with the establishment of distinct neuroretinal, retinal, pigmented-epithelial and optic-stalk progenitor domains, suggesting redundant functions during retinal determination. Pax2; Pax6 compound mutants display a dose-dependent reduction in the expression of the melanocyte determinant Mitf, accompanied by transdifferentiation of retinal pigmented epithelium (RPE) into neuroretina (NR) in Pax2(-/-); Pax6(+/-) embryos, which strongly resembles the phenotype of Mitf-null mutants. In Pax2(-/-); Pax6(-/-) OVs Mitf fails to be expressed and NR markers occupy the area that usually represents the Mitf(+) RPE domain. Furthermore, both, Pax2 and Pax6 bind to and activate a MITF RPE-promoter element in vitro, whereas prolonged expression of Pax6 in the Pax2-positive optic stalk leads to ectopic Mitf expression and RPE differentiation in vivo. Together, these results demonstrate that the redundant activities of Pax2 and Pax6 direct the determination of RPE, potentially by directly controlling the expression of RPE determinants.

Animals↗
PubMed2003

Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis.

Mammalian epidermis is maintained by stem cells that have the ability to self-renew and generate daughter cells that differentiate along the lineages of the hair follicles, interfollicular epidermis and sebaceous gland. As stem cells divide infrequently in adult mouse epidermis, they can be visualised as DNA label-retaining cells (LRC). With whole-mount labelling, we can examine large areas of interfollicular epidermis and many hair follicles simultaneously, enabling us to evaluate stem cell markers and examine the effects of different stimuli on the LRC population. LRC are not confined to the hair follicle, but also lie in sebaceous glands and interfollicular epidermis. LRC reside throughout the permanent region of the hair follicle, where they express keratin 15 and lie in a region of high alpha6beta4 integrin expression. LRC are not significantly depleted by successive hair growth cycles. They can, nevertheless, be stimulated to divide by treatment with phorbol ester, resulting in near complete loss of LRC within 12 days. Activation of Myc stimulates epidermal proliferation without depleting LRC and induces differentiation of sebocytes within the interfollicular epidermis. Expression of N-terminally truncated Lef1 to block beta-catenin signalling induces transdifferentiation of hair follicles into interfollicular epidermis and sebocytes and causes loss of LRC primarily through proliferation. We conclude that LRC are more sensitive to some proliferative stimuli than others and that changes in lineage can occur with or without recruitment of LRC into cycle.

Animals↗
PubMed2004

SOX9 specifies the pyloric sphincter epithelium through mesenchymal-epithelial signals.

Gastrointestinal (GI) development is highly conserved across vertebrates. Although several transcription factors and morphogenic proteins are involved in the molecular controls of GI development, the interplay between these factors is not fully understood. We report herein the expression pattern of Sox9 during GI development, and provide evidence that it functions, in part, to define the pyloric sphincter epithelium. SOX9 is expressed in the endoderm of the GI tract (with the exclusion of the gizzard) and its derivate organs, the lung and pancreas. Moreover, SOX9 is also expressed at the mesoderm of the pyloric sphincter, a structure that demarcates the gizzard from the duodenum. Using retroviral misexpression technique, we show that Sox9 expression in the pyloric sphincter is under the control of the BMP signaling pathway, known to play a key role in the development of this structure. By misexpressing SOX9 in the mesoderm of the gizzard, we show that SOX9 is able to transdifferentiate the adjacent gizzard epithelium into pyloric sphincter-like epithelium through the control of mesodermal-epithelial signals mediated in part by Gremlin (a modulator of the BMP pathway). Our results suggest that SOX9 is necessary and sufficient to specify the pyloric sphincter epithelial properties.

Animals↗
PubMed2006

A key role for the HLH transcription factor EBF2COE2,O/E-3 in Purkinje neuron migration and cerebellar cortical topography.

Early B-cell factor 2 (EBF2) is one of four mammalian members of an atypical helix-loop-helix transcription factor family (COE). COE proteins have been implicated in various aspects of nervous and immune system development. We and others have generated and described mice carrying a null mutation of Ebf2, a gene previously characterized in the context of Xenopus laevis primary neurogenesis and neuronal differentiation. In addition to deficits in neuroendocrine and olfactory development, and peripheral nerve maturation, Ebf2 null mice feature an ataxic gait and obvious motor deficits associated with clear-cut abnormalities of cerebellar development. The number of Purkinje cells (PCs) in the Ebf2 null is markedly decreased, resulting in a small cerebellum with notable foliation defects, particularly in the anterior vermis. We show that this stems from the defective migration of a molecularly defined PC subset that subsequently dies by apoptosis. Part of the striped cerebellar topography is disrupted due to cell death and, in addition, many of the surviving PCs, that would normally adopt a zebrin II-negative phenotype, transdifferentiate to Zebrin II-positive, an unprecedented finding suggesting that Ebf2 is required for the establishment of a proper cerebellar cortical map.

Animals↗
PubMed1992

Retinal fate and ganglion cell differentiation are potentiated by acidic FGF in an in vitro assay of early retinal development.

One of the earliest events in vertebrate eye development is the establishment of the pigmented epithelium and neural retina. These fundamentally different tissues derive from the invaginated optic vesicle, or optic cup. Even after achieving a fairly advanced state of differentiation, the pigmented epithelium exhibits the same potential as the optic cup in that it can "transdifferentiate" into neural retina. C. M. Park and M. J. Hollenberg (Dev. Biol. 134, 201-205, 1989) discovered that administration of basic fibroblast growth factor, coupled with retinal removal, could trigger this transformation in vivo. We have developed a quantitative in vitro assay to study the role(s) of the fibroblast growth factor (FGF) family in this phenomenon and more generally in early retinal development. We found that several aspects of the process, including inhibition of pigmented epithelium differentiation, proliferation, and conversion to a retinal fate, were not strictly correlated. Both acidic and basic FGFs were found to potentiate all aspects of the process, with acidic FGF being 4 to 20 times more potent than basic FGF for inhibition of pigmentation and induction of retinal antigens. Depending upon its concentration, acidic FGF induced from 40% to 80% of the cells in the explants to produce antigens normally expressed by retinal ganglion cells, the first cell type to be generated in retinal development. Expression of such a ganglion cell marker could be directly stimulated in non-dividing cells as well as in dividing cells, indicating that conversion from the pigmented epithelial to retinal fate did not require cell division. These data suggest that acidic FGF, or a related molecule, may function in establishment of retinal fate from the optic cup. This effect may be directly or indirectly mediated by induction of retinal ganglion cell fate among multipotent progenitor cells.

Animals↗
PubMed1995

The role of Pax-6 in eye and nasal development.

Small eye (Sey) mice homozygous for mutations in the Pax-6 gene have no lenses and no nasal cavities. We have examined the ontogeny of eye and nasal defects in Sey/Sey embryos and have related the defects seen to the pattern of Pax-6 mRNA expression in the mouse during normal eye and nasal development. There are two principal components of the early eye, the neural ectoderm of the optic vesicle, which forms the retina, and the overlying surface ectoderm, which forms the lens and cornea. By studying these interacting tissues in normal and Sey/Sey embryos, we have identified processes for which Pax-6 is important and can thus suggest possible roles for the Pax-6 gene. Pax-6 is essential for the formation of lens placodes from surface ectoderm. In normal development, early Pax-6 mRNA expression in a broad domain of surface ectoderm is downregulated, but expression is specifically maintained in the developing lens placode. Moreover, other Pax-6-expressing tissues are frequently those that have can transdifferentiate into lens. Thus, phenotype and expression together suggest a role for Pax-6 in lens determination. At least some functions of Pax-6 can be separated from the influence of other tissues. Early Sey/Sey optic vesicles are abnormally broad and fail to constrict proximally. These defects occur prior to the time of lens placode formation and probably reflect a requirement for Pax-6 in neural ectoderm. In surface ectoderm domains, where Pax-6 expression is known to be independent of the presence of an optic vesicle, Pax-6 function is required for the maintenance of its own transcription. The mutual dependency of lens and optic vesicle development can also be studied using the Small eye mutation. Using region-specific markers we find that, in the morphologically abnormal Sey/Sey optic vesicles, aspects of normal proximo-distal specification nevertheless persist, despite the complete absence of lens. Like the lens, the nasal cavities develop from ectodermal placodes that normally express Pax-6 mRNA, fail to form in Sey/Sey mice and show Pax-6-dependent Pax-6 mRNA regulation. Analysis of patterns of programmed cell death and absence of nasal region expression from an Msx-1 transgene in Sey/Sey embryos suggest a requirement for Pax-6 in the transition from presumptive nasal ectoderm to placode, and that Msx-1, or genes regulating it, are possible targets for Pax-6.

Animals↗
PubMed1997

Involvement of programmed cell death in morphogenesis of the vertebrate inner ear.

An outstanding challenge in developmental biology is to reveal the mechanisms underlying the morphogenesis of complex organs. A striking example is the developing inner ear of the vertebrate, which acquires a precise three-dimensional arrangement of its constituent epithelial cells to form three semicircular canals, a central vestibule and a coiled cochlea (in mammals). In generating a semicircular canal, epithelial cells seem to 'disappear' from the center of each canal. This phenomenon has been variously explained as (i) transdifferentiation of epithelium into mesenchyme, (ii) absorption of cells into the expanding canal or (iii) programmed cell death. In this study, an in situ DNA-end labeling technique (the TUNEL protocol) was used to map regions of cell death during inner ear morphogenesis in the chicken embryo from embryonic days 3.5-10. Regions of cell death previously identified in vertebrate ears have been confirmed, including the ventromedial otic vesicle, the base of the endolymphatic duct and the fusion plates of the semicircular canals. New regions of cell death are also described in and around the sensory organs. Reducing normal death using retrovirus-mediated overexpression of human bcl-2 causes abnormalities in ear morphogenesis: hollowing of the center of each canal is either delayed or fails entirely. These data provide new evidence to explain the role of cell death in morphogenesis of the semicircular canals.

Animals↗
PubMed1997

rZIP, a RING-leucine zipper protein that regulates cell fate determination during Dictyostelium development.

rZIP is an approx. 32 kDa, multi-domain protein of Dictyostelium discoideum whose structural motifs include a RING (zinc-binding) domain, a leucine zipper, a glutamine repeat, an SH3-binding region and a consensus phosphorylation site for MAP kinase. In vitro, rZIP forms homodimers and interacts specifically with the SH3 domain(s) of the Nck adaptor protein. rZIP is expressed maximally during cell differentiation at approximately equivalent levels in all cells. Disruption of the rZIP gene rzpA results in altered cellular aggregation, impaired slug migration, and aberrant patterning of prespore and prestalk cells, the major progenitor classes. In rzpA- strains, prespore-specific genes are overexpressed and prestalk expression zones are reduced. Conversely, constitutive overexpression of rzpA markedly decreases prespore-specific gene expression and significantly increases the expression of prestalk-specific genes. Further, induced transdifferentiation of prespore cells into prestalk cells is inhibited in rzpA-slugs. In light of these patterning defects, we suggest that the RING/zipper protein rZIP plays an important role in early cell fate decisions in Dictyostelium, acting as a positive regulator of prestalk differentiation and an inhibitor of prespore differentiation.

Amino Acid Sequence↗
PubMed1998

The homeobox-containing gene Wariai regulates anterior-posterior patterning and cell-type homeostasis in Dictyostelium.

We have identified a Dictyostelium gene, Wariai (Wri), that encodes a protein with a homeobox and seven ankyrin repeats; both domains are required for function. A null mutation results in a more than doubling of the size of the prestalk O (pstO) compartment, one of the anterior prestalk compartments lying along the anterior-posterior axis of the migrating slug. There is a concomitant decrease in the more posterior prespore domain and no change in the more anterior prestalk A (pstA) and prestalk AB (pstAB) domains. wri null cells also have a morphological defect consistent with an increase in the pstO cell population. Wri itself is preferentially expressed in the pstA but not the pstO compartment, raising the possibility that Wri regulation of pstO compartment size is nonautonomous. Analysis of chimeric organisms is consistent with this model. Development in Dictyostelium is highly regulative, with cells within the prestalk and prespore populations being able to transdifferentiate into other cells to maintain proper cell-type proportioning. Our results suggest that Wri controls cell-type proportioning, possibly by functioning as a negative regulator of a pathway mediating pstO cell differentiation and controlling the mechanism of homeostasis regulating the size of one or more of the cell-type compartments. Our results also suggest that homeobox gene regulation of anterior-posterior axis patterning may have evolved prior to the evolution of metazoans.

Amino Acid Sequence↗