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PubMed2004

Regulation of gene expression in cardiomyocytes by thyroid hormone and thyroid hormone analogs 3,5-diiodothyropropionic acid and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid].

The heart is an important target of thyroid hormone actions. Only a limited number of cardiac target genes have been identified, and little is known about their regulation by T(3) (3,3',5-triiodothyronine) and thyroid hormone analogs. We used an oligonucleotide microarray to identify novel cardiac genes regulated by T(3) and two thyroid hormone analogs, 3,5-diidodothyropropionic acid (DITPA) and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid]. DITPA binds with lower affinity than T(3) to thyroid hormone receptor alpha1 and beta1 isoforms, whereas CGS 23425 binds selectively to beta1. Fluorescent-labeled cDNA was prepared from cultured heart cells maintained in medium stripped of thyroid hormone ("hypothyroid" control) or treated with T(3), DITPA, and CGS 23425 at concentrations 5 times their respective K(d) values for 48 h. The arrays were scanned and analyzed using an analysis of variance program. Sixty-four genes were identified that were >1.5 times up- or down-regulated by one of the treatments with P < 0.05. The genes regulated by T(3) and DITPA were nearly identical. Thirteen genes were differentially regulated by CGS 23425. Genes encoding contractile proteins, Ca(2+)-ATPase of sarcoplasmic reticulum and several proteins of mitochondrial oxidative phosphorylation, were up-regulated by T(3) and DITPA but not by CGS 23425. These results indicate that some, but not all, of the actions of thyroid hormone analogs can be explained by differences in gene activation.

Animals↗

PubMed2004

Novel mode of deoxyribonucleic acid recognition by thyroid hormone receptors: thyroid hormone receptor beta-isoforms can bind as trimers to natural response elements comprised of reiterated half-sites.

Thyroid hormone receptors (TRs) regulate gene expression by binding to specific DNA sequences, denoted thyroid hormone response elements (TREs). The accepted paradigm for TRs proposes that they bind as homo- or heterodimers to TREs comprised of two AGGTCA half-site sequences. In the prototypic TRE, these half-sites are arranged as direct repeats separated by a four-base spacer. This dimeric model of TR binding, derived from analysis of artificial DNA sequences, fails to explain why many natural TREs contain more than two half-sites. Therefore, we investigated the ability of different TR isoforms to bind to TREs possessing three or more half-sites. We report that the TRbeta isoforms (TRbeta0, TRbeta1, TRbeta2), but not TRalpha1, can bind to reiterated DNA elements, such as the rat GH-TRE, as complexes trimeric or greater in size. The TRbeta0 isoform, in particular, formed homo- and heterotrimers (with the retinoid X receptor) with high efficiency and cooperativity, and TRbeta0 preferentially used reporters containing these reiterated elements to drive gene expression in vivo. Our data demonstrate that TRbeta isoforms can form multimeric receptor complexes on appropriately reiterated DNA response elements, providing a functional distinction between the TR isoforms and an explanation for TREs possessing three or more half-sites.

Animals↗

PubMed2000

The mechanism of action of thyroid hormones.

Thyroid hormone is essential for normal development, differentiation, and metabolic balance. Thyroid hormone action is mediated by multiple thyroid hormone receptor isoforms derived from two distinct genes. The thyroid hormone receptors belong to a nuclear receptor superfamily that also includes receptors for other small lipophilic hormones. Thyroid hormone receptors function by binding to specific thyroid hormone-responsive sequences in promoters of target genes and by regulating transcription. Thyroid hormone receptors often form heterodimers with retinoid X receptors. Heterodimerization is regulated through distinct mechanisms that together determine the specificity and flexibility of the sequence recognition. Amino-terminal regions appear to modulate thyroid hormone receptor function in an isoform-dependent manner. Unliganded thyroid hormone receptor represses transcription through recruitment of a corepressor complex, which also includes Sin3A and histone deacetylase. Ligand binding alters the conformation of the thyroid hormone receptor in such a way as to release the corepressor complex and recruit a coactivator complex that includes multiple histone acetyltransferases, including a steroid receptor family coactivator, p300/CREB-binding protein-associated factor (PCAF), and CREB binding protein (CBP). The existence of histone-modifying activities in the transcriptional regulatory complexes indicates an important role of chromatin structure. Stoichiometric, structural, and sequence-specific rules for coregulator interaction are beginning to be understood, as are aspects of the tissue specificity of hormone action. Moreover, knockout studies suggest that the products of two thyroid hormone receptor genes mediate distinct functions in vivo. The increased understanding of the structure and function of thyroid hormone receptors and their interacting proteins has markedly clarified the molecular mechanisms of thyroid hormone action.

Animals↗

PubMed2006

PCB-related alteration of thyroid hormones and thyroid hormone receptor gene expression in free-ranging harbor seals (Phoca vitulina).

Persistent organic pollutants are environmental contaminants that, because of their lipophilic properties and long half-lives, bioaccumulate within aquatic food webs and often reach high concentrations in marine mammals, such as harbor seals (Phoca vitulina). Exposure to these contaminants has been associated with developmental abnormalities, immunotoxicity, and reproductive impairment in marine mammals and other high-trophic-level wildlife, mediated via a disruption of endocrine processes. The highly conserved thyroid hormones (THs) represent one vulnerable endocrine end point that is critical for metabolism, growth, and development in vertebrates. We characterized the relationship between contaminants and specific TH receptor (TR) gene expression in skin/blubber biopsy samples, as well as serum THs, from free-ranging harbor seal pups (n = 39) in British Columbia, Canada, and Washington State, USA. We observed a contaminant-related increase in blubber TR-alpha gene expression [total polychlorinated biphenyls (capital sigmaPCBs); r = 0.679; p < 0.001] and a concomitant decrease in circulating total thyroxine concentrations (capital sigmaPCBs; r = -0.711; p < 0.001) . Consistent with results observed in carefully controlled laboratory and captive feeding studies, our findings suggest that the TH system in harbor seals is highly sensitive to disruption by environmental contaminants. Such a disruption not only may lead to adverse effects on growth and development but also could have important ramifications for lipid metabolism and energetics in marine mammals.

Adipose Tissue↗

PubMed1999

Thyroid hormone and thyroid hormone analogues in the treatment of heart failure.

The thyroid hormone analogue DITPA is a promising potential new treatment for heart failure. Although the mechanism of action is incompletely determined, it is clear that DITPA improves systolic as well as diastolic function. It is also clear that the effects of DITPA are intrinsic to the muscle and not the result of changes in the structure or geometry of the left ventricle. On the basis of these experimental studies, we applied to the USA Food and Drug Administration for an Investigational New Drug application to study the use of DITPA in patients. These studies are currently in progress. While we await the outcome of these clinical trials, it is important to emphasize that even if the end-point is not a new drug to treat heart failure, our investigations are based on a systematic evaluation integrating biochemistry and physiology. We believe that this is the way to approach the problem of developmental pharmacology.

Animals↗

PubMed1999

Oligodendrocyte development and thyroid hormone.

Thyroid hormone plays an important role in brain development and is essential to ensure a normal myelination. The effects of thyroid hormone are mediated by nuclear thyroid hormone receptors, which act as ligand-regulated transcription factors. There are several isoforms encoded by two genes, alpha and beta. Developmental studies have shown that alpha isoforms are widely expressed in the fetal brain, while beta isoforms expression is more restricted with a dramatic increase that begins at birth in the rat. Remarkably, receptor number reaches maximal levels by postnatal day 10, when serum thyroid hormone levels also peak and myelination is the most prominent event in the developing rat brain. Likewise, oligodendrocyte precursor cells express alpha isoforms and expression of the beta isoforms is confined to the differentiated oligodendrocytes, suggesting that these isoforms might mediate different thyroid hormone effects in the oligodendrocyte lineage. Thyroid hormone acts at multiple steps in the development of oligodendrocytes: (a) Early in development, it can function as an instructive signal for the generation of oligodendrocytes and enhance the proliferation of the committed preprecursor oligodendrocyte cells. (b) Thyroid hormone regulates the number of oligodendrocyte generated by directly promoting their differentiation. Since oligodendrocytes are produced in vitro after the same period in culture regardless of whether thyroid hormone was added to the cultures, it has been suggested that thyroid hormone is required for neither the timing nor the generation of oligodendrocytes, but is necessary to achieve adequate oligodendrocyte numbers. (c) Finally, thyroid hormone increases morphological and functional maturation of postmitoitic oligodendrocytes by stimulation of the expression of various myelin genes.

Animals↗

PubMed1981

Beta 2 receptor-mediated stimulation of Friend erythroleukemia cell growth by thyroid hormones.

Thyroid hormones are known to enhance normal erythroid colony growth (CFUE) and this enhancement depends on a functional beta 2-adrenergic receptor mechanism. we investigated the response of Friend cells to thyroid hormones, catecholamines, and other compounds influencing cellular cAMP activity. The thyroid hormones L-T3, L-T4, and "reverse T3" stimulated erythroleukemia colony growth in a serum-substituted methylcellulose culture system with peak activity at 10(-7) M. Various beta-adrenergic compounds enhanced Friend leukemia colony growth; however, the alpha-adrenergic agonist phenylephrine was inactive. Dibutyryl cyclic AMP and the phosphodiesterase inhibitor theophylline also enhanced Friend leukemia colony formation. Adrenergic antagonists with beta 2 specificity abrogated the stimulatory effect of L-T3, L-T4, and of "reverse T3" at equimolar concentrations. These experiments demonstrate that thyroid hormones, beta-adrenergic agonists, the phosphodiesterase inhibitor theophylline, and dbcAMP have a direct effect on the proliferation of Friend erythroleukemia cells. We conclude that thyroid hormones' action requires a functioning beta 2-adrenergic receptor mechanism. Thyroid hormones directly modulate the growth of neoplastic erythroid cells in a manner consistent with their effects on normal erythropoiesis.

Animals↗

PubMed1996

Syndrome of resistance to thyroid hormone: insights into thyroid hormone action.

Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are transcription factors that act by altering patterns of gene expression. Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in the TR beta gene. Biochemically, the syndrome is defined by elevated circulating levels of free thyroid hormones due to reduced target tissue responsiveness and normal, or elevated, levels of thyroid-stimulating hormone (TSH). This "inappropriate" TSH elevation contrasts with the situation in hyperthyroidism, where the pituitary secretion of TSH is suppressed. Patients with RTH usually present with goiter and an euthyroid or mildly hypothyroid metabolic state. Thus, pituitary resistance results in hypersecretion of TSH, which compensates, at least in part, for hormone resistance in peripheral tissues. Despite this compensation, clinical effects of RTH can include short stature, delayed bone maturation, hyperactivity, learning disabilities, and hearing defects, as well as variable features of hyper- and hypothyroidism. With the exception of a single sibship, which harbored a deletion of the entire coding sequence of the TR beta gene and a recessive pattern of inheritance, all other cases of RTH have been inherited in an autosomal dominant manner or have been de novo heterozygous mutations of the TR beta gene. The dominant pattern of inheritance is explained by the functional properties of the mutant receptors which act in a dominant negative manner to block the activity of normal TR alpha and TR beta receptors. Now that a large number of different RTH mutations have been identified, it is striking that the mutations are clustered within restricted domains in the carboxyterminal region of the receptor. Mutations in these regions have been shown to preserve critical receptor functions such as dimerization and DNA binding, while inactivating other activites such as T3 binding and transcriptional activation. The examination of patients with RTH and their mutated receptors has provided important insights into the mechanisms of thyroid hormone action, the structure-function relationship of the receptors, and the molecular mechanisms of dominant negative activity.

Amino Acid Sequence↗

PubMed1988

Adrenergic inhibition of the stimulatory effect of 3,5,3'-triiodothyronine on calcium accumulation and cytoplasmic free calcium concentration in rat thymocytes. Further evidence in support of the concept that calcium serves as the first messenger for the prompt action of thyroid hormone.

Thyroid hormone produces a prompt, plasma membrane-mediated increase in several metabolic functions in the rat thymocyte. These effects of thyroid hormone require calcium and are inhibited by the beta-adrenergic antagonist alprenolol. In the present study, the interrelationship between thyroid hormone and adrenergic agents, and the concept that calcium serves as the first messenger for the rapid action of thyroid hormone in the rat thymocyte are further examined. T3 produced a very rapid and dose-related increase in both 45 calcium accumulation and cytoplasmic free calcium concentration. These effects of T3, like its other calcium-dependent and prompt effects, were inhibited by beta-, but not by alpha-, adrenergic antagonists. Studies with selective beta-adrenergic agents revealed that the inhibitory effect was beta-1 in nature. In addition, beta-adrenergic agonists were found to promote additively T3 action, possibly through their beta-2 activity. Hence, the present study provides further support for the concept that calcium serves as the first messenger in the rapid, plasma membrane-mediated action of thyroid hormone in the rat thymocyte.

Adrenergic alpha-Antagonists↗

PubMed1997

Regulation of anterior pituitary galanin gene expression by thyroid hormone.

Thyroid hormone is required for basal and estrogen-induced expression of anterior pituitary galanin. Steady-state anterior pituitary galanin mRNA levels decreased 6-fold in hypothyroid rats after 3 weeks of treatment. Similarly, hypothyroidism resulted in a 2.6-fold decrease in estrogen induction of galanin gene expression. The effect of thyroid hormone on anterior pituitary galanin gene expression appears to be exerted, at least in part, at the pituitary itself. Transient expression assays in GH3 cells suggest the involvement of transcriptional mechanisms in the regulation of galanin gene expression by thyroid hormone. A region between -41 and -132 bp upstream of the transcriptional start site confers thyroid hormone responsiveness to the galanin gene. Gel-mobility shift assays show specific binding of 'SPI-like' proteins in GH3 nuclear extracts to this region of the galanin gene. This binding was greatly enhanced by thyroid hormone.

Animals↗

PubMed1993

[Pituitary resistance to thyroid hormone].

Thyroid hormone resistance syndromes are characterized by unresponsiveness of target tissues to thyroid hormone and include a group of three disorders: generalized resistance, selective pituitary resistance and peripheral resistance. These patients are identified because they have persistently increased serum thyroxin (T4), triiodothyronine (T3) and normal or elevated thyrotropin levels. In case of selective pituitary resistance to thyroid hormone (PRTH), the peripheral tissues exhibit a normal response to T4 and T3 so that hyperthyroidism ensues. Recently cloning of T3 receptor has allowed detection of mutations in the T3 binding region of the T3 receptor gene, which provides strong evidence that P.R.T.H. represents part of the spectrum of generalized resistance to T3, rather than a separate entity.

Adolescent↗

PubMed1994

Kinetic parameters of plasma thyroid hormone and thyroid hormone receptors in a dwarf and control line of chicken.

Sex-linked dwarf chickens have in plasma low triiodothyronine (T3) levels and slightly raised thyroxine (T4) concentrations and are functional hypothyroid. The kinetic parameters of T4 and T3 were investigated using 125I-labeled hormones. In addition the nuclear T3-receptors in the liver were examined using a radioreceptorassay and Scatchard analysis. Four-week-old dwarf (dw) and normal (Dw) chickens were injected with 125I-labeled T3 or T4 and blood samples taken 60, 120, 180, and 300 min after 125I-T3 injection and 120, 240, 360, and 480 minutes after 125I-T4 treatment. Labeled T4 and T3 and the degradation products were separated by paper chromatography. After the paper strips were dried, the iodinated compounds were visualized and counted in the gamma counter. The kinetic parameters, the half-life time (T1/2), the apparent distribution volume (Vd) and the metabolic clearance rate (MCR) were calculated using the natural base logarithm values of the measured radioactivity plotted against time and used for linear regression. T4 was cleared from circulation more slowly in dwarf than in control chicks and reflected a longer T1/2 (21.8%) and a reduced MCR (45%). The Vd tended to be lower (34.7%) in dwarfs. While the T1/2 of T3 was longer (28.1%) in dwarf chickens than in control animals, the MCR for T3 was considerably increased (31.8%). This results from an increased Vd (63.1%) in the dwarf chicks. The T3-receptor study in the liver of dwarf and non-dwarf chickens from Week 1 to Week 4 posthatching revealed that the total capacity and the affinity constant of the binding sites were comparable in dwarf and normal chickens. However, the occupancy of the receptors was higher in the dwarf animals.

Animals↗

PubMed2003

A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone.

Thyroid hormone (T3) regulates bone turnover and mineralization in adults and is essential for skeletal development during childhood. Hyperthyroidism is an established risk factor for osteoporosis. Nevertheless, T3 actions in bone remain poorly understood. Patients with resistance to thyroid hormone, due to mutations of the T3-receptor beta (TRbeta) gene, display variable phenotypic abnormalities, particularly in the skeleton. To investigate the actions of T3 during bone development, we characterized the skeleton in TRbetaPV mutant mice. TRbetaPV mice harbor a targeted resistance to thyroid hormone mutation in TRbeta and recapitulate the human condition. A severe phenotype, which includes shortened body length, was evident in homozygous TRbetaPV/PV animals. Accelerated growth in utero was associated with advanced endochondral and intramembranous ossification. Advanced bone formation resulted in postnatal growth retardation, premature quiescence of the growth plates, and shortened bone length, together with increased bone mineralization and craniosynostosis. In situ hybridization demonstrated increased expression of fibroblast growth factor receptor-1, a T3-regulated gene in bone, in TRbetaPV/PV perichondrium, growth plate chondrocytes, and osteoblasts. Thus, the skeleton in TRbetaPV/PV mice is thyrotoxic and displays phenotypic features typical of juvenile hyperthyroidism.

Animals↗

PubMed1991

Increased rat femur osteocalcin mRNA concentrations following in vivo administration of thyroid hormone.

Thyroid hormone has a direct resorptive effect on bone. Thyroid hormone therapy in doses that suppress pituitary TSH production result in a reduction in bone density. Osteocalcin is a bone matrix protein. Serum levels are a sensitive marker for bone turnover and are increased in hyperthyroid patients. In order to establish an animal model to study the effects of thyroid hormone on bone turnover, we measured rat femur osteocalcin mRNA following in vivo administration of thyroid hormone. Young CD rats weighing 60-90 g were given daily ip injections of T3, T4, or saline (control) for 12 days. Blood was obtained for radioimmunoassays, and RNA was extracted from femurs and analyzed by Northern blot using a 60-mer synthetic oligonucleotide probe corresponding to bases 360-420 of rat osteocalcin mRNA, labeled with [32P] ATP by 5'-end-labeling. Serum TSH concentrations were suppressed to subnormal levels by the lowest doses of T3 and T4, and to undetectable levels by the higher doses. Increases in serum T3 and T4 concentrations were proportional to the dose of each administered hormone. T3, 5 and 10 micrograms/100 g body weight, resulted in a 43% and 62% increase in osteocalcin mRNA, respectively. T4, 5, 10, and 20 micrograms/100 g body weight, resulted in a 35%, 47%, and 135% increase in osteocalcin mRNA, respectively. These data demonstrate that in vivo administration of either T4 or T3 to young rats results in a significant dose-dependent increase in femur osteocalcin mRNA concentrations.

Animals↗

PubMed2002

Environmental incubation factors influence embryonic thyroid hormones.

Thyroid hormone responses in embryonic avian species are of two types, developmental and metabolic. Many studies have characterized the developmental function of the turkey embryonic thyroid, but few have characterized the metabolic function. Therefore, the purpose of this study was to describe the response of turkey embryonic thyroid hormones to three environmental factors. We proposed that embryonic thyroids from different genetic backgrounds would respond differently to changes in maternal diet and incubation temperature. Lines of turkeys known to have different embryonic growth and survival were examined in the current study. These eggs differ in egg weight, eggshell conductance, hatchling weight and organ maturity at the time of hatching. Eggs were produced throughout a 20 wk laying period and embryos were sampled at monthly intervals. Half of the hens producing the eggs were fed additional iodide in their diets, then, subsequently, half of each dietary treatment and line combination were incubated at either 36.8 C or 37.5 C to prolong the incubation period. Embryos were sampled during the final week of incubation when thyroid hormones become elevated to effect maturation and survival functions in turkey embryos. Embryonic thyroxine (T4) and triiodothyronine (T3) levels were assayed by RIA and compared among the treatments. Line, diet, and incubation period interacted to affect the levels of T4, T3 and T3 to T4 ratios in the turkey embryonic during late incubation. It was concluded that environmental factors can affect circulating thyroid hormone levels in turkey embryos, thus affecting metabolic functions, and the possibility exists to manipulate these circulating levels using environmental incubation conditions to improve hatchability.

Animal Feed↗

PubMed1989

Thyroid hormone nuclear receptors and their role in the metabolic action of the hormone.

Thyroid hormone nuclear receptor molecules have been characterized as proteins of approximately 49,000 molecular weight existing in cells attached to chromatin and with 4000-8000 copies per nucleus. They bind T3 with Ka of 0.2 X 10(10) l/mol and show microheterogeneity on isoelectric focusing. Hormone responsiveness varies with receptor content in the nucleus and occupancy of receptor by T3. Recent investigations have shown that the receptors are part of the v-erbA related super family of nuclear hormone receptors. At least two types of T3 receptors (TR) exist, one coded by a gene on chromosome 3 (TR beta) and a second coded on chromosome 17 (hTR alpha). Receptors are low in the fetus and, in the adult, are dramatically reduced by starvation, illness and glucagon. Receptors function through binding of T3 or other hormone analogs to a domain in the carboxyl portion of the protein, and binding of the receptor-T3 complex through 'DNA-fingers' to specific response elements as enhancers and located in the 5'-flanking DNA of thyroid hormone responsive genes. Extensive studies on regulation of rat growth hormone have suggested binding of receptor or associated factors to several positions in the 5'-flanking DNA, and recent studies suggest that a crucial area may be a 15 bp segment between bases -179 and -164. Abnormal receptors are believed to be responsible for the syndrome of generalized resistance to thyroid hormone action, but it is yet unclear as to which form (or forms) of the receptor is abnormal in this syndrome.

Amino Acid Sequence↗

PubMed2003

Regulation of mitochondrial biogenesis by thyroid hormone.

Thyroid hormone (T3) has a profound effect on mitochondrial biogenesis. T3-regulated gene expression is mediated by thyroid hormone receptor (TR) binding to thyroid hormone response elements (TREs). In concert with the action of various coactivators and corepressors this interaction leads to a modulation of the chromatin structure and subsequently to a modulation of gene expression of adjacent target genes. However, as numerous genes are endogenously regulated by T3, and a TRE appears to be absent in their regulatory elements, a TR-independent pathway of T3-mediated gene regulation is likely. In this review, we discuss the direct mechanisms of TR-dependent regulation of gene expression on the nuclear and mitochondrial genome by T3. We also summarise recent observations on an indirect mechanism of T3 action via intermediate factor(s). We discuss the regulation of nuclear respiratory factor 1 (NRF-1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) by T3, suggesting NRF-1 and PGC-1alpha as attractive candidates for an intermediate factor of T3 action in vivo.

Adaptation, Physiological↗

PubMed1993

Differential expression of mutant and normal beta T3 receptor alleles in kindreds with generalized resistance to thyroid hormone.

Thyroid hormone resistance (THR) is primarily an autosomal dominant inherited disease characterized by resistance of pituitary and peripheral tissues to the action of thyroid hormone. We investigated whether the heterogeneous phenotypic features that occur not only among kindreds but also within the same kindred might be due to the expression of differing ratios of mutant and normal receptors in tissues. Using an allele-specific primer extension method, we determined the relative expression of normal and mutant mRNAs from the fibroblasts of affected and unaffected members of two kindreds with TRH: A-H and N-N. While two affected members of A-H, as expected, had nearly equal amounts of normal and mutant hTR beta mRNA, two other members had mutant mRNA levels that accounted for at least 70% of the hTR beta mRNA. Phenotypic variability within and between kindreds with generalized resistance to thyroid hormone GRTH may be due to this differential expression of the mutant and wild type mRNA. Furthermore, when several clinical parameters of THR were compared in several affected members from two kindreds with GRTH, we found that two cases in one kindred exhibited a high mutant-to-normal hTR beta ratio and had considerably more bone resistance during their development. In certain kindreds with THR, differing ratios of normal and mutant hTR receptors may be age and growth related and may account for the reported attenuation of phenotypic symptoms with age.

Adolescent↗