BIOLOGICAL OVERVIEW

When comparing dorsal-ventral polarity between invertebrates like Drosophila and vertebrates like Xenopus one is in for a truely topsy-turvy experience. At some point in the dim recesses of evolutionary history, a split occurred as to the preferred location of the nerve cord. In invertebrates, the nerve cord develops ventrally, while in vertebrates, it develops dorsally. In effect, the wiring (nerve cord) that is protected by the vertebrate backbone, runs without such protection along the invertebrate's "front."

The common ancestor of vertebrates and invertebrates appears to have already developed a mechanism for dorsal-ventral polarity, used by all subsequent animals with nerve cords. At what point did dorsal-ventral polarity shift? This is analagous to a shift in the magnetic pole, as though for one phylum, all the compasses started pointing south. Biologists focus both on the earliest multicellular organisms for an answer, animals that evolved during the Cambrian Period's so-called "explosion of life," and on the importance of the larval stage of development.

Selection for a switch in dorso-ventral polarity would have been easier to make in the larval stage of development, rather than at a later stage. Such a larva would have been "mature" as a larva and would have forgone an adult stage. The discovery of vertebrate-invertebrate homology in mechanisms for dorsal-ventral polarity has sent biologists to the fossil record, hunting for clues as to that common ancestor. One has to look further back in evolution than insects and worms. Coelenterates incorporate many of the prototypical design elements found in higher animals. sog is an important element of dorsal-ventral polarity in the fly. It appears to function as an antagonist to the activity of Decapentaplegic, leading to the subdivision of the dorsal region of the fly into amnioserosa [Images] and dorsal ectoderm (Francis, 1994).

Although invertebrate sog and vertebrate chordin are homologs, a comparison of their effects on polarity seems to be a paradox. Either of the two genes (sog expressed ventrally in flies and chordin expressed dorsally in frogs), can promote ventral development in Drosophila, and sog, like chordin, can promote dorsal development in Xenopus.

In spite of their phylogenetically conserved function, the maternal mechanisms by which sog and dpp are activated in abutting territories in fly embryos (i. e., direct transcriptional threshold responses to the Dorsal morphogen gradient) appear to differ fundamentally from those leading to the complementary activation of chordin and BMP-4 in frog embryos (i.e., Wnt and Activin-like induction of goosecoid expression in the Spemann organizer, leading to chordin expression dorsally, and FGF plus a low Activin-like signal inducing BMP-4 expression ventrally). In contrast, once the primary zygotic response genes sog/chordin and dpp/BMP-4 are expressed in abutting territories, they specify neural vs. non-neural ectoderm through a highly conserved mechanism. SOG functions by preventing DPP from autoactivating (reinforcing its own expression). How does SOG function as a DPP antagonist? As Chordin has been shown to bind BMP-4 with high affinity (Picolla, 1996), the mechanism of Chordin/Sog function may be to bind and sequester BMP-4/DPP in an inactive form (Biehs, 1996).

Tolloid has been shown to target Short gastrulation. Tolloid, a putative metalloprotease related to BMP-1, enhances DPP function, while SOG, an ortholog of the Xenopus organizer Chordin, inhibits DPP function. Tolloid is secreted and requires a protelytic processing step for activation. The removal of the N-terminal prodomain is not catalyzed by TLD itself, since it is removed from a putative TLD protease null mutant. Most of the TLD in embryos is in the nonprocessed form. Using epistasis tests and a Xenopus secondary axis induction assay, it has been shown that TLD negates the inhibitory effects of SOG/CHD on DPP/BMP-type ligands. Ventral overexpression in Xenopus of either a dominant negative BMP4 receptor, or a cleavage mutant of either BMP4, Noggin, Chordin, or Short gastrulation induces secondary axes in 80%-100% of injected embryos. However, when CHD or SOG mRNA are coinjected, together with an equimolar amount of TOD mRNA, secodary axis induction is blocked, suggesting that TLD is capable of inhibiting SOG or CHD function. Activated TLD is unable to inhibit secondary axis induction mediated by Noggin, the dominant negative BMP receptor, or a cleavage mutant of BMP. In transient transfection assays, TLD cleaves SOG; this cleavage is stimulated by DPP. It is proposed that formation of the embryonic DPP activity gradient involves the opposing effects of SOG inhibiting DPP, and TLD processing SOG to release DPP from the inhibitory complex (Marques, 1997).

Dorsal-ventral patterning within the embryonic ectoderm of Drosophila requires two type I TGFbeta receptors, Tkv and Sax, as well as two TGFbeta ligands, Dpp and Scw. In embryos lacking dpp signaling, increasing the level of Tkv activity promotes progressively more dorsal cell types, while activation of Sax alone has no phenotypic consequences. However, Sax activity synergizes with Tkv activity to promote dorsal development. To determine the interrelationship between the signaling pathways downstream of the Tkv and Sax receptors, an assay was carried out of the phenotypic consequences of activating each signaling pathway separately in embryos that lack dpp expression. Increasing levels of activation of Tkv signaling recapitulate embryonic dorsal-ventral pattern, as measured by the dosage-dependent production of dorsal epidermal and amnioserosal cell fates. In contrast, activation of the Sax signaling pathway alone does not promote formation of any dorsal structures. However, the activated Sax receptor synergizes with the activated Tkv receptor in production of both dorsal epidermis and amnioserosal cell fates. From these data it is concluded that, while the functions of both receptors are necessary for in vivo patterning, elevation of Tkv signaling can bypass the requirement for Sax signaling. Furthermore, the data indicate that Sax signaling is dependent on Tkv signaling for phenotypic consequences and that Sax signaling elevates the biological response to a given level of Tkv signaling (Neul, 1998).

Functional experiments suggest the two receptors have different ligands: Dpp acts through Tkv, and Scw acts through Sax. Furthermore, Sog, a negative regulator of this patterning process, preferentially blocks Scw activity. To establish functional interactions between the Scw ligand and the Sax receptor, use was made of the ability of scw mutant embryos to produce amnioserosa in response to injection of either DPP or SCW mRNAs. Injection of mRNA encoding a dominant-negative Sax receptor is able to block the biological activity of injected SCW mRNA but is unable to block the activity of injected DPP mRNA. These findings were extended by showing that scw function is required for the ability of a chimeric receptor containing the extracellular domain of Sax fused to the intracellular domain of Tkv to rescue a tkv mutant. Taken together, these results strongly suggest that Scw is an obligate component of the Sax ligand. Furthermore, because ventral expression of scw in cells that do not express dpp is sufficient to rescue a scw mutant, Scw-DPP heterodimers appear not to be essential for the generation of wild-type pattern, raising the possibility that Scw homodimers are the in vivo ligand for the Sax receptor (Neul, 1998).

Injection of SOG mRNA blocks the biological response of scw mutants to injection of SCW mRNA, but not to injection of DPP mRNA. These results strongly suggest that Sog, which has been genetically characterized as a negative regulator of Dpp activity, functions primarily to modulate Scw activity over the dorsal-ventral axis. These data thus suggest that an activity gradient of dpp results from the differential spatial modulation of Scw activity by Sog. This could happen by either of two mechanisms. One possibility is that the existence of a local ventral source for Sog and the presence of a 'sink' for Sog in the dorsal regions of the embryo (the cleavage of Sog by Tld) could result in a ventral-to-dorsal gradient of Sog. The binding of Sog to Scw could thereby result in the formation of a reciprocal dorsal-to-ventral gradient of scw activity. A second model for the action of Sog posits that Sog facilitates the directional diffusion of the Scw ligand from the lateral to the dorsal regions of the embryo. Specifically, Sog binding to Scw shields the ligand from binding to its ubiquitously localized receptors and thereby allows the Scw-Sog complex to diffuse in the perivitelline space. Dorsally located Tolloid then cleaves Sog, releasing the Scw ligand from the inhibitor. The action of Sog would thus lead to increased dorsal localization of Scw and increased activity of the Sax pathway, ultimately resulting in formation of amnioserosa. This facilitated diffusion model implies that one function of Sog is to elevate Dpp/Scw signaling dorsally. This model would directly explain the reduction in amnioserosa observed in sog mutants and would account for the cell nonautonomous function of Scw, revealed by ventral injections of SCW mRNA. Moreover, this model could also provide an explanation for a puzzling aspect of the phenotype of embryos that lack the nuclear gradient of dorsal gene product. Such dorsalized embryos have a pattern of zygotic gene expression around the embryonic circumference that is similar to that of the most dorsal cells in the wild-type embryo. However, only a small number of cells in dorsalized embryos differentiate as amnioserosa; the great majority of cells in these embryos differentiate as dorsal ectoderm. An increase in dpp gene dosage in dorsalized embryos is sufficient to increase the number of amnioserosal cells. Thus, it appears that despite the pattern of gene expression in dorsalized embryos, the level of dpp/scw signaling is not sufficient to fate amnioserosa. Dorsalized embryos do not express sog; thus, the lack of 'facilitated diffusion' of the Scw ligand mediated by Sog could be the cause of this phenotype (Neul, 1998 and references).

It is proposed that the original function of Dpp might have been to mediate dose-independent cell fate decisions. The ability of Dpp to function in a dose-dependent manner was acquired evolutionarily by the recruitment of a second signaling system whose output could modulate Tkv activity, but whose biological function was dependent on Dpp. The genetic compartmentalization inherent within this circuitry would have ensured the increased evolutionary capacity of such a patterning system. Specifically, genetic alterations in components of the modulatory signaling pathway could lead to significant phenotypic variability without disruption of the original cell fate choice mediated by Dpp. Thus, this genetic circuitry could have been a component in the generation of diverse body plans (Neul, 1998).

Integrins modulate Sog activity in the Drosophila wing

Morphogenesis of the Drosophila wing depends on a series of cell-cell and cell-extracellular matrix interactions. During pupal wing development, two secreted proteins, encoded by the short gastrulation (sog) and decapentaplegic (dpp) genes, vie to position wing veins in the center of broad provein territories. Expression of the Bmp4 homolog dpp in vein cells is counteracted by expression of the secreted Bmp antagonist sog in intervein cells; this results in the formation of straight veins of precise width. A screen was performed for genetic interactions between sog and genes encoding a variety of extracellular components and interactions were uncovered between sog and myospheroid (mys), multiple edematous wing (mew) and scab (scb), which encode ßPS, alphaPS1 and alphaPS3 integrin subunits, respectively. Clonal analysis reveals that integrin mutations affect the trajectory of veins inside the provein domain and/or their width and that misexpression of sog can alter the behavior of cells in such clones. In addition, a low molecular weight form of Sog protein has been shown to bind to alphaPS1ßPS. Sog can diffuse from its intervein site of production into adjacent provein domains, but only on the dorsal surface of the wing, where Sog interacts functionally with integrins. Finally, it has been shown that Sog diffusion into pro-vein regions and the reticular pattern of extracellular Sog distribution in wild-type wings requires mys and mew function. It is proposed that integrins act by binding and possibly regulating the activity/availability of different forms of Sog during pupal development through an adhesion independent mechanism (Araujo, 2003).

sog mRNA is confined to intervein cells during pupal development. Since Sog protein diffuses during early embryonic development, however, it was of interest to see whether Sog might also travel from its intervein site of production into the provein region during pupal development. Pupal wings were stained with the anti-Sog antiserum and a dynamic pattern of Sog protein distribution was observed, including vein competent domains as well as intervein cells. Anti-Sog staining is initially patchy (around 20 hours apf), stronger on the dorsal surface and mostly restricted to intervein cells. Shortly thereafter (22-26 hours apf), Sog staining spreads into provein cells on the dorsal surface of the wing, at which point it is excluded only from the most central vein-proper cells. On the corresponding ventral surface, however, Sog staining remains excluded from the entire provein region throughout pupal development (i.e., up to 34 hours apf). Between 26 and 30 hours apf, Sog staining fills all the provein domains on the dorsal surface, with increased levels of staining observed at the provein/intervein border. At 30 hours apf, Sog staining diminishes overall and becomes restricted to intervein cells and hemocytes running in the middle of the vein. Since sog mRNA is detectable only in intervein cells during the examined pupal period, it is concluded that Sog protein must be delivered to cells within the provein territory on the dorsal surface by some form of passive diffusion or active transport (Araujo, 2003).

Because diffusion of Sog into provein domains is restricted to the dorsal surface of the wing where integrins interact with Sog, it was asked whether integrins play a role in regulating the distribution of Sog protein on the dorsal surface of pupal wings. Marked mys minus or mew minus clones were generated in an otherwise wild-type background and Sog staining was examined. In control wings, double-labeling with anti-ß integrin and anti-Sog antisera confirmed that the dorsally restricted pattern of reticular Sog staining extends beyond ß-integrin staining into provein domains. By contrast, Sog staining has a patchy intracellular appearance in dorsal mys minus clones, and is excluded from wild-type provein cells on the dorsal surface that are adjacent to mys minus clones. In such cases where mys minus clones are located on one side of a provein domain, Sog is still able to enter the provein region from the opposite mys⁺ side of the same vein. These results demonstrate that mys is required for diffusion or transport of Sog into the vein competent domain. Consistent with the observation that only dorsally located integrin minus clones can alter the course of veins, it was found that only dorsal mys minus clones modify Sog distribution in the pupal wing. Similarly altered Sog staining was observed within mew minus clones on the dorsal wing surface resulting in punctate rather than reticular staining and lack of Sog diffusion into the provein region. These results demonstrate that the ßPS and alphaPS1 integrins play an important role in determining the distribution of Sog protein in the pupal wing (Araujo, 2003).

In this study, three primary lines of evidence are provided that integrins play an important role in regulating Bmp signaling in provein regions of the pupal wing: (1) integrin minus clones generated on the dorsal surface of the wing alter the trajectory and/or width of adjacent veins; (2) a truncated form of Sog present in pupal wings binds to alphaPS1; (3) diffusion of Sog into provein domains, which is restricted to the dorsal surface of the wing, depends on integrin function. Cumulatively, these results strongly suggest that the ability of Sog to diffuse or to be transported into provein regions on the dorsal surface depends on an interaction with integrins (Araujo, 2003).

Consistent with Sog interacting genetically with integrins to alter the course of veins on the dorsal surface of the wing, it was found that the alphaPS1 and ßPS-integrins are required for the diffusion or transport of Sog from dorsal intervein cells where sog mRNA is expressed into adjacent provein regions. Since alphaPS1 binds Sog, this physical interaction may contribute to regulating the distribution of Sog. The 8B anti-Sog antiserum used in this study, that recognizes Sog protein in intervein cells and inside the provein domain, detects an epitope located near the second cystein repeat (CR2). Consequently, Sog fragments that diffuse or that are delivered to provein cells must be either full length, which weakly binds to alphaPS1 in co-immunoprecipitation experiments, or fragments that contain CR2. The truncated Supersog-like fragment that binds strongly to alphaPS1 in coimmunoprecipitation experiments should not be recognized by the 8B antiserum. Therefore, integrins may differentially regulate the distribution of Sog fragments on the dorsal surface of the pupal wing, restraining the movement of broad spectrum Bmp inhibitory Sog fragments (such as Supersog-like molecules) and allowing or mediating transport of other fragments to provein cells, such as full-length Sog, which also has a vein inhibitory function. Unfortunately, it is not possible currently to examine the diffusion of Supersog-like fragments directly because the 8A antiserum is not suitable for staining pupal wings. These findings suggest that integrins regulate the delivery or diffusion of active Sog protein from intervein cells into the vein competent domain. In contrast to the dorsally restricted functions of integrins required for vein development, the adhesive functions of integrins depends on subunits functioning on both surfaces of the wing (Araujo, 2003).

There are several possible mechanisms by which interaction with integrins could modulate Sog activity in pupal wings. Elevated sog expression results in vein truncation, while misexpression of dpp induces ectopic veins, indicating that sog restricts vein formation by opposing Bmp signals emanating from the center of the vein (Yu, 1996). One possibility is that such a Bmp inhibitory form(s) of Sog must interact with integrins in order to diffuse or be transported into provein domains (on the dorsal surface of the wing only). This hypothesis would be consistent with the finding that veins appear to be attracted to integrin minus clones. Such a vein repulsive form(s) of Sog would presumably act as a Bmp antagonist (Araujo, 2003).

According to the simple model in which integrins are essential for delivering a Bmp inhibitory form of Sog to provein cells, one would expect that integrin minus and sog minus clones would generate similar phenotypes in which veins deviated towards the mutant clones and/or broadened within them. However, sog minus clones induce meandering of veins (Yu, 1996) -- veins show only a weak tendency to track along the outside of sog minus clones, in contrast to integrin minus clones, which bend or widen veins in a more dramatic fashion. One possible explanation for the differences between the sog minus and integrin minus phenotypes is that there are several different endogenous forms of Sog in pupal wings, which might exert opposing activities. If multiple Sog fragments exert effects on vein development, some providing repulsive and others attractive activities on vein formation, the differences between the behaviors of sog- and integrin- clones could be explained by a repulsive (Bmp inhibitory) form(s) of Sog selectively requiring an interaction with integrins. The possibility that a positive Bmp-promoting activity of Sog might also be present that acts as a vein attractant has precedent in that a positive Sog activity has been proposed to explain a requirement for Sog in activating expression of the Dpp target gene race in early embryos. Structure/function studies of Sog have also revealed a potential Bmp promoting form of Sog, which is longer than Supersog forms. According to this model, altering the balance between repulsive and attractive Sog activities would generate different vein phenotypes. In the total absence of sog, both repulsive and attractive activities would be lost, generating a mild meandering vein phenotype in which neither attraction nor repulsion clearly dominates, as is observed in sog minus clones (Yu, 1996). If an interaction with integrins were required only for production or delivery of Bmp inhibitory forms of Sog into the vein, then integrin minus clones, which still contain the Bmp-activating forms of Sog, could exert a net attractive influence on veins, leading to more pronounced deviation of veins toward the clones. This hypothesis is consistent with vein phenotypes observed associated with integrin minus clones that cross over veins or run along both sides of the vein, such as narrowing, bending and wandering of veins; these phenotypes are similar to those observed in correspondingly located sog minus clones. The existence of different Sog fragments bearing opposing activities would also explain the different phenotypes obtained upon ectopic Sog expression in some sog^EP lines (Yu, 1996), such as sporadic ectopic vein material between L3 and L2 and meandering L2 veins in addition to vein loss in other areas (Araujo, 2003).

Another possible explanation for the differences between the sog minus and integrin minus phenotypes is that integrins may regulate the activity of extracellular signals in addition to Sog. One hint of such an activity is that when a scb minus clone falls within the provein area, the vein splits around the border of the clone in a cell autonomous fashion. Since this later phenotype is enhanced by ectopic sog expression in veins (e.g., in a sog^EP background), alphaPS3 may normally promote Bmp signaling within the vein. Although the identity of such potential targets is unknown, candidates would include Bmps (e.g. Dpp or Gbb) or Bmp receptors. Further analysis will be needed to explain the basis for the different behaviors of sog minus and integrin minus clones, as well as the variations observed in different integrin minus clones (Araujo, 2003).

In summary, it is proposed that Sog fragments with differential activities may regulate vein formation. The vein bending phenotype observed in the absence of alphaPS1 would result from a remaining attractive Sog activity that outweighs the activity of a repulsive form of Sog, which can no longer be delivered from intervein cells. Since ßPS integrin forms heterodimers with both alphaPS1 and alphaPS3 mys would be expected to be required for the activity of both alphaPS chains. Consistent with this expectation, the phenotype of mys minus clones (i.e., broad poorly defined veins) resembles a hybrid of those observed for mew minus and scb minus clones (Araujo, 2003).

Endocytosis has been shown to play an important role in the establishment of Bmp activity gradients. The endocytic pathway has been implicated in transport of Dpp between cells by transcytosis during larval wing development. During early embryonic development, formation of a Sog protein gradient in dorsal regions also relies on the action of Dynamin, although in this preblastoderm context, it has been proposed that endocytosis limits the dorsal diffusion of Sog, which is essential for the partitioning of the dorsal ectoderm into epidermis and amnioserosa. Vertebrate alpha3ß Integrin (E. deRobertis, personal communication to Araujo, 2003) has been shown to bind to the Xenopus Sog counterpart Chordin in vitro, leading to endocytosis of Chordin (Araujo, 2003).

Although the possible regulation of Sog endocytosis by integrins is not addressed in this current study, the altered distribution of Sog within integrin minus clones is suggestive of such a role. Reticular Sog staining, which outlines the cell perimeter is lost in integrin minus clones on the dorsal surface, leaving only a punctate intracellular staining. This mis-localization of Sog implicates integrins in internalizing and/or trafficking of Sog to the cell surface. Because appropriately located integrin minus clones also block the accumulation of Sog in adjacent pro-vein domains, the observed defects in Sog distribution between the surface and the cytoplasm may underlie the failure to deliver Sog to vein competent cells. The endocytic pathway could promote the transport of Sog to pro-vein cells by a mechanism similar to that proposed to be involved in the transport of Dpp along the AP axis during larval stages. Alternatively, endocytosis could function to limit Sog diffusion as is the case during embryogenesis. According to this latter scenario, integrins would normally prevent or reduce Sog endocytosis because integrins are necessary for delivery of Sog to pro-vein cells. Integrins have been shown to play a direct role in endocytosis of viral particles and in mediating membrane traffic through the endocytic cycle. Indirect mechanisms for integrin-mediated endocytosis may also exist that would not involve endocytosis of the integrin receptor itself, but of other components that regulate Sog trafficking. Further analysis will be necessary to investigate whether Drosophila integrins regulate delivery of Sog to endocytic vesicles or transport of Sog through the endocytic pathway to adjacent cells (Araujo, 2003).

The modulatory effect of integrins on Sog activity described in this paper are likely to be mediated by dpp and/or gbb signaling because existing evidence indicates that Sog is a dedicated modulator of Bmp signaling. In addition, the phenocritical period for mys and sog interaction coincides with that for interaction between sog and dpp (Yu, 1996). The existence cannot be excluded of an additional role of integrins in regulating vein formation through another pathway, such as the Egf and Notch pathways, which have been shown to exert important roles on vein development. However, the integrin minus clonal phenotypes described in this manuscript are observed only on the dorsal surface and all known components of the Egfr pathway promote vein development on both surfaces of the wing (Araujo, 2003).

mys^nj42 and scb¹ were found suppress the thickened vein phenotype of tkv¹ mutants, which raises the possibility of a direct interaction between integrins and a Bmp receptor involved in wing vein development. The vein splitting and vein thickening scb minus clonal phenotypes are reminiscent of tkv mutant phenotypes, which derive from a positive requirement for Bmp signaling for vein formation inside the vein competent domain and a negative ligand titrating function that limits the range of Bmp diffusion into the intervein territory adjacent to the provein domain. The fact that scb is expressed in both vein and intervein territories is consistent with a dual action of scb. Additional experiments will be necessary to investigate whether scb plays a direct role in modulating Bmp receptor activity (Araujo, 2003).

Diffusion of putative growth factors and the shaping of their activity gradients have been the focus of intense interest since Alan Turing formulated the concept of morphogens (Turing, 1952: see 'The chemical basis of morphogenesis'. Philos. Trans. R. Soc. Lond. B Biol. Soc. 237: 37-72). Recently, several groups have described mechanisms to explain how soluble factors can create morphogen gradients. These include: (1) degradative proteolysis and a retrieval role for endocytosis in creating the early embryonic Sog gradient; (2) regulated endocytosis of wingless extracellular transport of Wg in membrane bound argosomes; (3) planar transcytosis (as is required for Dpp movement in the wing imaginal disc), and (4) the formation of thin cell extensions (cytonemes) that deliver Dpp over several rows of cells. Protein-protein interactions in the extracellular milieu, such as those described here, may also be capable of modulating the magnitude and spatial pattern of Bmp activity, working independently or in conjunction with other mechanisms (Araujo, 2003).

GENE STRUCTURE

Bases in 5' UTR - 709

Bases in 3' UTR - 604 Bases in 3' UTR - 604

PROTEIN STRUCTURE

Amino Acids - 1038

Structural Domains

sog is predicted to encode a protein with an internal signal sequence (functioning in the secretion process) and a large extracellular domain containing four repeats of a novel motif defined by the spacing of 10 cysteine residues; these repeat motifs are distantly related to domains present in thrombospondin and procollagen. One or more of these cysteine repeats can be liberated by proteolytic cleavage of the primary SOG protein (Francois, 1994). One unusual difference between SOG and Chordin is that SOG contains a Type II transmembrane domain near its N terminus, whereas CHD contains a traditional signal sequence. SOG is secreted from Drosophila cultured cells and is glycosylated, suggesting that despite the presence of a transmembrane domain, at least a fraction of the SOG protein is released from cells which is consistent with its nonautonomous behavior in early embryogenesis (Marques, 1997). Thrombospondin and procollagen are known to bind TGF-beta, the vertebrate homolog of Decapentaplegic, by a domain homologous to SOG (Francois, 1994).

date revised: 18 February 2024 

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