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Biomedical subjects

I B Fritz

Publications and source records attributed to I B Fritz.

At least 55 records · Page 3Linked to original sources
PubMed1986

Extracellular matrix components and testicular peritubular cells influence the rate and pattern of Sertoli cell migration in vitro.

We report the patterns of migration of Sertoli cells plated on specific substrata, and the influences of testicular peritubular cells on these processes. Data presented indicate that while peritubular cells readily spread when explanted onto Type I collagen, Sertoli cells do not. A delay of 4 to 6 days occurs after Sertoli cells are plated before they begin to migrate randomly to form plaque-like monolayers on Type I collagen. These processes are dependent upon the synthesis and subsequent deposition of laminin and/or Type IV collagen by Sertoli cells, and are independent of fibronectin. A different behavior occurs when reconstituted mixtures of purified Sertoli cells and pertiubular cells are sparsely plated onto Type I collagen. Peritubular cells rapidly spread to form chains of cells between Sertoli cell aggregates. Sertoli cells then migrate on the surfaces of the peritubular cells, culminating in the formation of cable-like structures between aggregates. Evidence is presented that the Sertoli cell migration to form "cables" under these conditions is dependent upon fibronectin synthesized by peritubular cells, and is independent of the presence of laminin or Type IV collagen. We discuss the possible relevance of these data to the role which precursors of peritubular cells may play in determining the behavior of Sertoli cell precursors in vivo during tubulogenesis, or in the remodelling of the seminiferous tubule which occurs during different stages of the cycle of the seminiferous epithelium in spermatogenesis.

Animals↗
PubMed1986

Cell-substratum and cell-cell interactions promote testicular peritubular myoid cell histotypic expression in vitro.

Peritubular cells, prepared from seminiferous tubules from testes of 20-day-old-rats, were seeded onto different substrata and cultured under varying conditions. When plated onto polystyrene or glass surfaces, peritubular cells assumed a typical fibroblast-like cell shape and cell association pattern, together with a fibroblast-like migration behavior. They maintained high rates of proliferation even after achieving confluency. In contrast, when peritubular cells were plated onto a seminiferous tubule biomatrix (ST-biomatrix) surface, they spread to form a continuous cell layer having a myoepithelioid histotype similar to that of peritubular myoid cells in the intact seminiferous tubule. The characteristics of the myoepithelioid histotype described include a squamous, polyhedral cell shape; a cobblestone-like cell association pattern, with closely apposing or slightly overlapping cell borders, and a very low mitotic index. When peritubular cells were plated onto laminin, collagen, fibronectin, heparin, or a liver biomatrix, a fibroblast-like pattern resulted, indicating that ECM components listed and liver biomatrix are unable to substitute for ST-biomatrix in maintaining normal myoepithelioid characteristics in vitro. In cocultures of Sertoli cells plated on top of peritubular cells, the peritubular cells directly in contact with Sertoli cell aggregates developed a myoepithelioid histotype, whereas peritubular cells in regions not in direct contact had a fibroblast-like histotype. The data are discussed in relation to the possible role of cell-cell interactions, and cell-substratum interactions, in the acquisition and stabilization of the histotype of peritubular cells in the seminiferous tubule during development.

Animals↗
PubMed1986

Identification of a non-mitogenic paracrine factor involved in mesenchymal-epithelial cell interactions between testicular peritubular cells and Sertoli cells.

Seminiferous peritubular cells have previously been shown to secrete a protein termed P-Mod-S which modulates the functions of Sertoli cells. The present study provides an initial characterization of P-Mod-S and examines the actions of P-Mod-S on Sertoli cells. Gel filtration chromatography demonstrates that P-Mod-S has an apparent molecular weight of 70 000 that could not be dissociated to a lower molecular weight form. A 40- to 90-fold purification of P-Mod-S was obtained with a predicted half maximal effective concentration for Sertoli cells of less than 10(-9) M. Through an analysis of the actions of P-Mod-S on Sertoli cells it is demonstrated that P-Mod-S stimulates the Sertoli cell to a greater extent than any single hormone or vitamin known to influence the cell. P-Mod-S maximally stimulates testicular transferrin and androgen-binding protein production by Sertoli cells, but does not stimulate levels of plasminogen activator activity. P-Mod-S also appears to induce the synthesis of several proteins that are not detected in control non-treated Sertoli cell cultures. One such protein whose synthesis was stimulated by P-Mod-S treatment of Sertoli cells was a component having a molecular mass of 20 kDa. This 20 kDa Sertoli cell-secreted protein was specifically immunoprecipitated with an antibody against an epididymal lactalbumin-like protein. This implies that P-Mod-S can induce Sertoli cells to synthesize and secrete a lactalbumin-like protein. P-Mod-S was found not to contain mitogenic activity. Data presented indicate that testicular peritubular cells synthesize and secrete a 70 kDa non mitogenic paracrine factor termed P-Mod-S which has a dramatic influence on Sertoli cell functions. Results are discussed with respect to modulation of epithelial (Sertoli) cell functions by components produced by mesenchymal (peritubular) cells.

Androgen-Binding Protein↗
PubMed1986

Hormonal stimulation alters the type of plasminogen activator produced by Sertoli cells.

Primary cultures of immature rat Sertoli cells, maintained in serum-free medium, secrete two types of plasminogen activator (PA). When cultured under basal conditions, the preparations predominantly produce PA having a relative molecular weight (Mr) of 45,000 to 48,000. This PA activity is inactivated by antiserum against urokinase-type PA. When Sertoli cells are stimulated by follicle-stimulating hormone (FSH) or by dibutyryl cyclic adenosine 3',5'-monophosphate (dbcAMP), PA secretion is increased. The PA produced under these conditions has an Mr of 70,000, and is inactivated by antiserum against tissue-type PA but not by antiserum against urokinase-type PA. We conclude that, under basal conditions, Sertoli cells primarily secrete PA having the characteristics of urokinase-like PA (mu PA), and that Sertoli cells stimulated by FSH or by dbcAMP predominantly produce PA having the properties of tissue-type PA (tPA). Segments of adult rat seminiferous tubules, at defined stages of the cycle of the seminiferous epithelium, also produce and secrete two types of PA into the medium when maintained in organ culture. Segments at all stages examined release primarily mu PA in preparations cultured under basal conditions. In contrast, segments cultured in the presence of FSH synthesize larger amounts of PA, predominantly of the tPA type. An additional protease, which is independent of plasminogen, is secreted by tubule segments stimulated by FSH. The activity of this novel protease is not detectable in cultures maintained under basal conditions. We discuss the data in relation to the possible role of proteases in the restructuring of the seminiferous tubule during spermatogenesis.

Animals↗
PubMed1986

Reflections on the evolution of the regulation of spermatogenesis.

We have developed the concept that mechanisms evolved very early for the modulation of spermatogenesis in response to changes in the external environment, and that these ancient control mechanisms were retained during subsequent evolution. In nearly all animals, the regulation of germinal cell development is postulated to be mediated through the control of gonadal somatic cell functions, associated with the creation and maintenance of an optimal milieu within the spermary of seminiferous tubule in which gametogenesis takes place. In primitive organisms, a small number of stages intervenes between environmental stimuli and subsequent alteration of gonadal somatic cell functions. In contrast, in more complex organisms, the number of intervening stages is greatly amplified and modulated via neuroendocrine mechanisms involving receptors, transducers, and various sorts of relays and messengers. The evolution of these neural and endocrine controls appears to have occurred in lock-step with the evolution of increasing layers of complexity of regulators of spermatogenesis. This is not unduly surprising, since the requirement to have functionally fertile male and female partners of the same species together at the same time and place would require considerable integration of behavioral and recognition mechanisms during courtship and mating. The nature of these neural mechanisms is likely to prove no less complex than that of mechanisms in the gonad required for successful gamatogenesis. The neuroendocrine regulation of spermatogenesis in starfish and in chordates is postulated to act in a manner completely homologous to the ways in which external environmental stimuli influence spermatogenesis in more primitive organisms. In both sets of cases, the gonadal somatic cells (nurse cells) are the ultimate targets which mediate the effective turning on or turning off of spermatogenesis. The hormone-responsive nurse cells are postulated to achieve this simply by creating a microenvironment in the vicinity of germinal cells which permits the expression of program required for development, or by failing to do so. In mammals, Sertoli cells and peritubular cells, only when optimally stimulated by hormones and paracine factors, are thought to form a functional unit which provides this necessary microenvironment. In less complex organisms, other nurse cell arrangements exist to nourish the syncytia of developing germ cells with the mixture of nutrients, salts, etc. required for a gametogenesis to take place in a protected milieu.

Animals↗
PubMed1985

Structural characterization of proteoglycans produced by testicular peritubular cells and Sertoli cells.

The structural characteristics of proteoglycans produced by seminiferous peritubular cells and by Sertoli cells are defined. Peritubular cells secrete two proteoglycans designated PC I and PC II. PC I is a high molecular mass protein containing chondroitin glycosaminoglycan (GAG) chains (maximum 70 kDa). PC II has a protein core of 45 kDa and also contains chondroitin GAG chains (maximum 70 kDa). Preliminary results imply that PC II may be a degraded or processed form of PC I. A cellular proteoglycan associated with the peritubular cells is described which has properties similar to those of PC I. Sertoli cells secrete two different proteoglycans, designated SC I and SC II. SC I is a large protein containing both chondroitin (maximum 62 kDa) and heparin (maximum 15 kDa) GAG chains. Results obtained suggest that this novel proteoglycan contains both chondroitin and heparin GAG chains bound to the same core protein. SC II has a 50-kDa protein core and contains chondroitin (maximum 25 kDa) GAG chains. A proteoglycan obtained from extracts of Sertoli cells is described which contains heparin (maximum 48 kDa) GAG chains. In addition, Sertoli cells secrete a sulfoprotein, SC III, which is not a proteoglycan. SC III has properties similar to those of a major Sertoli cell-secreted protein previously defined as a dimeric acidic glycoprotein. The stimulation by follicle-stimulating hormone of the incorporation of [35S]SO2(-4) into moieties secreted by Sertoli cells is shown to represent an increased production or sulfation of SC III (i.e. dimeric acidic glycoprotein), and not an increased production or sulfation of proteoglycans. Results are discussed in relation to the possible functions of proteoglycans in the seminiferous tubule.

Animals↗
PubMed1985

Androgen stimulation of Sertoli cell function is enhanced by peritubular cells.

Rates of production of androgen binding protein (ABP) declined during culture of purified Sertoli cell-enriched aggregates in serum-free minimal essential medium (MEM). This decline was partially prevented by the addition of testosterone to the medium, but not by 17 beta-estradiol addition. The androgen effect was greater in Sertoli cell aggregates in co-culture with peritubular cells than in Sertoli cell preparations depleted of peritubular cells. Initial rates of ABP production by purified Sertoli cell-enriched aggregates were also sustained when preparations were cultured in MEM supplemented with conditioned medium in which peritubular cells had been previously maintained. We interpret data presented to indicate that the stimulatory effects of peritubular cells on functions of Sertoli cells in co-culture, specifically sustained rates of ABP production, are mediated at least partially by component(s) synthesized by peritubular cells and secreted into the medium. We offer the hypothesis that androgens may influence Sertoli cells at two levels: (1) a direct action on Sertoli cells; (2) and indirect influence on Sertoli cells mediated by a direct action on peritubular cells, resulting in the formation of product(s) which modulate the rates of ABP synthesis.

Androgen-Binding Protein↗
PubMed1985

Testicular peritubular cells secrete a protein under androgen control that modulates Sertoli cell functions.

Peritubular cells of the seminiferous tubule synthesize component(s) that stimulate Sertoli cells in culture to increase the production of androgen-binding protein and testicular transferrin. The active peritubular cell component(s) are trypsin-sensitive, heat-sensitive, acid-stable molecule(s) having a molecular weight between 50,000 and 100,000. These specific factors(s) are referred to as P Mod-S to designate protein(s), produced by peritubular cells (P), that modulate the functions of Sertoli cells (S). The degree of stimulation by P Mod-S is comparable to that obtained by maximal hormonal stimulation of the synthesis of ABP and transferrin by Sertoli cells. Levels of P Mod-S secreted into the medium by primary cultures of peritubular cells are increased in the presence of testosterone. Comparable concentrations of 17 beta-estradiol do not stimulate peritubular cells to synthesize P Mod-S. Data are interpreted to indicate that androgens act on testicular peritubular cells to increase the formation of P Mod-S and that P Mod-S may modulate the properties of adjacent Sertoli cells. Findings are discussed in relation to the nature of mesenchymal-epithelial cell interactions in the seminiferous tubule and to the possible role of P Mod-S as a mediator of androgen actions of Sertoli cells.

Androgen-Binding Protein↗
PubMed1985

Cooperativity between Sertoli cells and testicular peritubular cells in the production and deposition of extracellular matrix components.

We examined the synthesis and deposition of extracellular matrix (ECM) components in cultures of Sertoli cells and testicular peritubular cells maintained alone or in contact with each other. Levels of soluble ECM components produced by populations of isolated Sertoli cells and testicular peritubular cells were determined quantitatively by competitive enzyme-linked immunoabsorbent assays, using antibodies shown to react specifically with Type I collagen, Type IV collagen, laminin, or fibronectin. Peritubular cells in monoculture released into the medium fibronectin (432 to 560 ng/microgram cell DNA per 48 h), Type I collagen (223 to 276 ng/microgram cell DNA per 48 h), and Type IV collagen (350 to 436 ng/microgram cell DNA per 48 h) during the initial six days of culture in serum-free medium. In contrast, Sertoli cells in monoculture released into the medium Type IV collagen (322 to 419 ng/microgram cell DNA per 48 h) but did not form detectable amounts of Type I collagen or fibronectin during the initial six days of culture. Neither cell type produced detectable quantities of soluble laminin. Immunocytochemical localization investigations demonstrated that peritubular cells in monoculture were positive for fibronectin, Type I collagen, and Type IV collagen but negative for laminin. In all monocultures most of the ECM components were intracellular, with scant deposition as extracellular fibrils. Sertoli cells were positive immunocytochemically for Type IV collagen and laminin but negative for fibronectin and Type I collagen. Co-cultures of peritubular cells and Sertoli cells resulted in interactions that quantitatively altered levels of soluble ECM components present in the medium. This was correlated with an increased deposition of ECM components in extracellular fibrils. The data correlated with an increased deposition of ECM components in extracellular fibrils. The data presented here we interpret to indicate that the two cell types in co-culture act cooperatively in the formation and deposition of ECM components. Results are discussed with respect to the nature of interactions between mesenchymal peritubular cell precursors and adjacent epithelial Sertoli cell precursors in the formation of the basal lamina of the seminiferous tubule.

Animals↗
PubMed1985

Immunolocalization of clusterin in the ram testis, rete testis, and excurrent ducts.

Clusterin, a glycoprotein that elicits cell aggregation, has previously been isolated from ram rete testis fluid, and has been partially characterized. In experiments reported, we have used monoclonal antibodies against clusterin in combination with indirect immunofluorescence microscopy to investigate the distribution of clusterin in the adult ram testis, rete testis, and excurrent ducts. Tissue blocks (5 mm3) were fixed in periodate/lysine/paraformaldehyde containing 0.1% glutaraldehyde and, after embedding, 5-microM sections were prepared for immunolocalization. In the testis, 2 basic patterns were observed: 1) strong to moderate staining for clusterin in the adluminal region with little staining in the basal region of the seminiferous epithelium and germinal cells; and 2) moderate staining throughout the seminiferous epithelium between germinal cells. In the rete testis, strong clusterin staining was localized intracellularly in the rete epithelial cells, most often associated with the luminal surface. In the epididymis, intracellular clusterin was localized in some principal cells of the caput epididymidis. The luminal surfaces and spermatozoa within the lumen were strongly positive. In the vas deferens, clusterin staining was associated with the luminal surface only. The presence of clusterin was clearly detected in unwashed isolated epididymal spermatozoa, but not in spermatozoa washed with phosphate-buffered saline containing 0.05% Tween 20.

Animals↗
PubMed1984

Fibronectin synthesis is a marker for peritubular cell contaminants in Sertoli cell-enriched cultures.

With indirect immunofluorescent microscopic techniques, we have shown that fibronectin is distributed primarily in or along the basal lamina of the seminiferous tubule boundary tissue in sections of testes from 20-day-old rats. Purified rat Sertoli cell-enriched aggregates, maintained in culture in the presence or absence of serum, exhibit no detectable immunofluorescence with fibronectin antibody, whereas purified peritubular cells in culture do have a positive reaction to fibronectin antibody. Peritubular cells in culture incorporate [35S] methionine into fibronectin which can be immunoprecipitated with a fibronectin antiserum, but Sertoli cells do not. We have used various criteria to estimate the degree of purity of Sertoli cell-enriched preparations. The presence of peritubular myoid cells in conventional Sertoli cell-enriched aggregates, cultured in the presence or absence of serum, can be detected with transmission electron microscopic examination, by the Feulgen staining procedure, and by the immunocytochemical identification of fibronectin. We describe a technique to purify Sertoli cells in conventional Sertoli cell-enriched preparations by treatment with hyaluronidase, resulting in a lesser number of peritubular cells by the above criteria, even in preparations cultured in the presence of serum. Data presented suggest that some of the products previously attributed exclusively to Sertoli cells in Sertoli cell-enriched preparations, particularly those cultured in the presence of serum, may have been contributed by peritubular cells.

Animals↗
PubMed1984

Extracellular matrix promotes rat Sertoli cell histotypic expression in vitro.

We describe procedures for the preparation of a cell-free seminiferous tubule biomatrix, and provide evidence demonstrating that this material constitutes a useful substratum for maintaining the normal architecture of Sertoli cells in primary culture. Seminiferous tubule biomatrix, which has the morphological appearance of a fibrillar network rich in filaments and amorphous substance, is shown to consist of about 50% protein, most of which is collagen and glycoproteins. Fibronectin and laminin are also present in the seminiferous tubule biomatrix, as judged by immunofluorescence microscopy. Sertoli cell aggregates plated on this substratum retain a cuboidal to columnar shape, spread very slowly to form a monolayer, and survive for at least 3 weeks when cultured in a hormone-free, serum-free, chemically defined medium. In contrast, Sertoli cells plated onto uncoated polystyrene readily spread to form a monolayer of flat squamous cells which do not survive as well. Other morphological and ultrastructural characteristics are described which indicate that cells cultured on the seminiferous tubule biomatrix more closely resemble those of Sertoli cells in vivo than do cells plated on uncoated plastic. These differences in cell structure, including the maintenance of normal polarity as indicated by the presence of basolateral tight junctional complexes, remain evident for periods of 10 to 14 days after plating Sertoli cells onto biomatrix substratum. Rates of DNA synthesis by immature Sertoli cells plated onto biomatrix are less than rates by cells plated onto uncoated plastic. The data are discussed in relation to the role of substratum in the preservation of normal functions and histotype of Sertoli cells.

Animals↗
PubMed1984

Autoimmune orchitis can be induced by thymic lymphocytes autosensitized against syngeneic sertoli cells in vitro.

Thymic lymphocytes from normal inbred Lewis/Wistar rats were cocultured with syngeneic Sertoli cell-peritubular cell preparations in the presence of heterologous or allogeneic serum. Thymic cells cultured in this manner bound to Sertoli cells, became autosensitized , and markedly altered syngeneic Sertoli cell surface properties and remodeling functions in vitro. In contrast, control thymic cells incubated with Sertoli cells in autologous or syngeneic serum did not become sensitized. Coculture of autosensitized thymic cells with syngeneic seminiferous tubule segments, or local transfer of such lymphocytes into syngeneic rat testes, resulted in intratubular infiltration by "light cells." Intratesticular injection of autosensitized thymic cells was followed by derangement of the seminiferous epithelium, and by morphologic changes characteristic of experimental autoimmune orchitis. Thymic cells incubated with Sertoli cells in autologous or syngeneic serum did not elicit these changes. Thymic cells incubated with peritubular cells in heterologous or autologous serum behaved like control thymocytes, and were not sensitized. Data presented indicate that thymic cells are potentially capable of recognizing syngeneic Sertoli cell self-antigens. We speculate that factors normally present in serum may inhibit the recognition by thymic lymphocytes of antigenic determinants present on Sertoli cells. We discuss the possibility that the modulation of interactions between immature thymic lymphocytes and Sertoli cells is implicated in the prevention of autoimmune reactions against the testis.

Animals↗
PubMed1984

Isoelectric forms of clusterin isolated from ram rete testis fluid and from secretions of primary cultures of ram and rat Sertoli-cell-enriched preparations.

Clusterin, a cell aggregating factor isolated from ram rete testis fluid (RTF), is shown to contain 14.7% hexoses, 13.6% glucosamine, and 7.9% sialic acid. The isoelectric point (pI) of the predominant electrophoretic form of clusterin from ram RTF is 3.7. After treatment with neuraminidase, the pI values become more basic, with the majority of the material being eluted from a chromatofocusing column at pH values between 4.9 and 5.1. Intact clusterin binds quantitatively to wheat germ agglutinin - Sepharose 6 MB, but after treatment with neuraminidase only 49% specifically binds. Clusterin isolated from proteins secreted by primary cultures of ram Sertoli-cell-enriched preparations was shown to have properties similar to those of intact clusterin isolated from ram RTF. In contrast, clusterin isolated from proteins secreted by primary cultures of rat Sertoli- or granulosa-cell-enriched preparations has isoelectric forms which more closely resemble those of neuraminidase-treated ram clusterin.

Animals↗
PubMed1983

Purification and characterization of a cell-aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid.

Clusterin has been purified from ram rete testis fluid by conventional techniques and by immunoaffinity chromatography. The molecule is characterized as a glycoprotein having a molecular mass of approximately 80,000 Da and an isoelectric point of 3.6. The purified protein retains the capacity to elicit clustering of cells in an in vitro assay. Under reducing conditions in the presence of sodium dodecyl sulfate, clusterin dissociates into subunits of about 40,000 Da. Heterogeneities in apparent molecular mass were eliminated after treatment of clusterin with neuraminidase. Gel filtration chromatography revealed that clusterin exists in dimeric and tetrameric forms under conditions of neutral pH and low salt concentrations. In the presence of 6 M urea, only the monomeric form is evident, with an apparent molecular mass of approximately 85,000 Da. Clusterin, which was found to contain 4.5% glucosamine, binds to concanavalin A-Sepharose and also to wheat germ agglutinin Sepharose. The amino acid composition of clusterin is reported. The possible cellular source of clusterin in rete testis fluid is discussed. It is shown that Sertoli cells in the seminiferous tubule are one potential source, since primary cultures of rat Sertoli cells secrete a protein having the same immunochemical and physical properties as clusterin isolated from ram rete testis fluid. Possible functions of clusterin are discussed.

Amino Acids↗
PubMed1983

The absence of specific interactions of Sertoli-cell-secreted proteins with antibodies directed against H-Y antigen.

Radiolabeled proteins secreted into the medium by rat Sertoli cells in primary culture have been examined for specific interactions with polyclonal and monoclonal antibodies directed against serologically detectable H-Y antigen(s). None of the proteins secreted by Sertoli cells reacted specifically with H-Y antibodies, as determined with immunoprecipitation procedures and immunoabsorbent affinity chromatography, followed by SDS gel electrophoresis. Radioactivity profiles of proteins obtained after reaction with H-Y antibodies were similar to those observed after treatment with nonimmune sera or with irrelevant antibodies. We obtained comparable findings with proteins secreted by the mouse cell line TM4, which is of presumptive Sertoli cell origin, and with proteins present in ram rete testis fluid. These and other findings presented do not support the contention that Sertoli cells secrete a protein having the properties of serologically detectable H-Y antigen as previously described.

Animals↗
PubMed1983

Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro.

Ram rete testis fluid is shown to elicit clustering of suspensions of Sertoli cells from testes of immature rats, TM-4 cells derived from mouse testis, and erythrocytes from several species. Details of bioassay procedures and characteristics of the phenomenon are reported. Concanavalin A and wheat germ agglutinin prevent aggregation elicited by rete testis fluid, and this inhibition is specifically prevented by alpha-methylmannoside and N-acetyl-glucosamine, respectively. Influences of rete testis fluid on cell aggregation are not dependent on exogenous calcium, but clustering is blocked by various metabolic inhibitors such as dinitrophenol. Rete testis fluid addition to mixed suspensions of erythrocytes and TM-4 cells is followed by separate aggregation of each cell types. Using aggregation of TM-4 cells suspended in simple medium at low density in rotation as a bioassy, we have determined which fractions in rete testis fluid retain activity. We have shown that a heat-stable, trypsin-sensitive protein, having an isoelectric point below pH 4.0, retains the capacity to aggregate cells. We discuss the possible functions of this protein, named clusterin, in cell interactions.

Animals↗