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PubMed2000

Role of transcriptional factor activation protein-1 in endogenous expression of the interleukin-1 beta gene involved in Porphyromonas gingivalis fimbria-stimulated bone resorption in the mouse calvarial system.

We previously suggested that endogenous interleukin-1 beta (IL-1 beta) produced by Porphyromonas gingivalis fimbriae stimulation in calvarial bone cell cultures plays a role in bone resorption as a major cytokine. Therefore, in the present study, we initiated experiments to clarify the stimulatory mechanism of IL-1 beta gene expression in fimbria-stimulated bone resorption. Fimbria-stimulated bone resorption was dramatically inhibited by curcumin, a potent inhibitor of activation protein-1 (AP-1). In fact, the fimbriae induced markedly both the expression of c-fos and c-jun genes and their protein production in the calvarial cells. In addition, a mixture of antisense oligonucleotides against c-fos and c-jun significantly inhibited not only the fimbria-induced expression of the IL-1 beta gene but also the fimbria-induced bone resorption. Therefore, the present study demonstrates that transcriptional factor AP-1 plays a functional role in P. gingivalis fimbria-stimulated bone resorption via endogenous IL-1 beta in the mouse calvarial system.

Animals↗

PubMed1992

Variable pattern of jun and fos gene expression in different hematopoietic cell lines during interleukin 3-induced entry into the cell cycle.

Jun (c-jun, jun-B and jun-D) and fos (c-fos, fos-B and fra) proteins dimerize to form the family of AP-1 transcriptional activators. If each dimer exhibits unique transactivating properties, then any phenotypic change should show a characteristic pattern of jun and fos expression. To test this hypothesis we have assessed jun and fos RNA expression after stimulation of the factor-dependent cell lines 32D and FDCP1. These hematopoietic progenitor lines become quiescent in G0/G1 after interleukin 3 (IL-3) deprivation, and upon stimulation synchronously enter the cell cycle. 32D cells respond to IL-3 with rapid induction of jun-B and c-fos, followed by induction of jun-D and fra-1, but no rise in c-jun expression. FDCP1 cells show a very different pattern, with induction of c-jun, jun-D and fra-1. To investigate the response of a single cell line to different physiological stimuli we used a 32D subclone engineered to respond to colony stimulating factor 1 (CSF-1). This subclone showed identical induction of jun and fos after stimulation with either CSF-1 or IL-3. The conservation of response of a single cell line, but the disparate patterns demonstrated by different cells, suggest a fundamental difference in both the regulation and function of the fos/jun complexes in these cells.

Blotting, Northern↗

PubMed1994

The retinoblastoma gene product RB stimulates Sp1-mediated transcription by liberating Sp1 from a negative regulator.

Studies have demonstrated that the retinoblastoma susceptibility gene product, RB, can either positively or negatively regulate expression of several genes through cis-acting elements in a cell-type-dependent manner. The nucleotide sequence of the retinoblastoma control element (RCE) motif, GCCACC or CCACCC, and the Sp1 consensus binding sequence, CCGCCC, can confer equal responsiveness to RB. Here, we report that RB activates transcription of the c-jun gene through the Sp1-binding site within the c-jun promoter. Preincubation of crude nuclear extracts with monoclonal antibodies to RB results in reduction of Sp1 complexes in a mobility shift assay, while addition of recombinant RB in mobility shift assay mixtures with CCL64 cell extracts leads to an enhancement of DNA-binding activity of SP1. These results suggest that RB is directly or indirectly involved in Sp1-DNA binding activity. A mechanism by which RB regulates transactivation is indicated by our detection of a heat-labile and protease-sensitive Sp1 negative regulator(s) (Sp1-I) that specifically inhibits Sp1 binding to a c-jun Sp1 site. This inhibition is reversed by addition of recombinant RB proteins, suggesting that RB stimulates Sp1-mediated transactivation by liberating Sp1 from Sp1-I. Additional evidence for Sp1-I involvement in Sp1-mediated transactivation was demonstrated by cotransfection of RB, GAL4-Sp1, and a GAL4-responsive template into CV-1 cells. Finally, we have identified Sp1-I, a approximately 20-kDa protein(s) that inhibits the Sp1 complexes from binding to DNA and that is also an RB-associated protein. These findings provide evidence for a functional link between two distinct classes of oncoproteins, RB and c-Jun, that are involved in the control of cell growth, and also define a novel mechanism for the regulation of c-jun expression.

3T3 Cells↗

PubMed2001

[Effects of Stat3 phosphorylation and expression of c-fos and c-jun proteins on hepatocarcinogenesis].

Expression of phosphorylated Stat3 (p-Stat3), c-fos and c-jun proteins was detected by immunohistochemical technique in 55 hepatocellular carcinomas (HCC) and their surrounding liver tissues. The results showed that the positive rates and signal intensity of p-Stat3, c-fos and c-jun protein in HCCs were significantly higher than those in pericarcinomatous tissues. The expressive intensity of c-fos and c-jun proteins was positively related to p-Stat3 expression in HCCs, whereas the positive correlation of expressive intensity was only observed between c-jun protein and p-Stat3 in pericarcinomatous tissues. The data suggest that the phosphorylation of Stat3 may be an early event in hepatocarcinogenesis; the overexpression of p-Stat3 protein, which activates c-fos and c-jun genes, may contribute to malignant transformation of hepatocytes; hepatocytes which expressed p-Stat3, c-fos or c-jun proteins may be potentially malignant pre-cancer cells in pericarcinomatous liver tissues.

Acute-Phase Proteins↗

PubMed1994

Differential induction of the two early genes c-jun and c-fos in weakly and strongly metastatic murine lymphoma cell lines.

Induction of the 2 early-response genes c-jun and c-fos was investigated in the weakly metastatic T-lymphoma Eb line and the related strongly metastatic lymphomacrophage ESb line to find possible correlations with their different in vitro and in vivo phenotypes. The response of c-jun was elicited by the protein kinase-C activators TPA and A23187 in ESb but not in Eb cells. A much lower response of c-fos was also found in Eb than in ESb cells, in this case by means of serum and the cAMP elevator forskolin. However, both TPA and the calcium ionophore A23187 were similarly effective in inducing fos-mRNA in both cell lines. The uncoupling of c-jun and c-fos induction in Eb, but not in ESb cells, as well as the uncoupling of c-fos response to different stimulators, point to a differential activation of these 2 early-response genes by the main signal transduction pathways in the 2 cell types. The coordinate/uncoordinate availability of the fos/jun heterodimer may confer distinct regulatory patterns on different target genes in ESb/Eb cells. Activation of these genes may underlie the distinct differentiation phenotypes and in vivo behavior of Eb/ESb cells.

Animals↗

PubMed1997

Presence of distinct AP-1 dimers in normal and transformed rat hepatocytes under basal conditions and after epidermal growth factor stimulation.

Activation of the transcriptional regulator AP-1, a dimeric complex formed of various combinations of Fos and Jun proteins, is a key step in the cellular response to mitogens. Because different dimers are believed to display different regulatory functions, we hypothesized that transformed cells that lack normal growth constraints might display AP-1 dimers that are different from those of normal cells. We therefore compared in primary and transformed rat hepatocytes (1) the composition of AP-1 dimers under basal conditions and (2) AP-1 induction by epidermal growth factor (EGF). Under basal conditions, AP-1 contained predominantly Jun homodimers in both cell types. However, whereas normal hepatocytes contained only JunD, both JunD and JunB were present in the AP-1 complex of 7777 cells. EGF treatment triggered almost identical programs of fos and jun gene activation at the messenger RNA (mRNA) level in both cell types, with an early accumulation of c-fos, c-jun, and junB mRNAs, but no change in junD mRNA levels. In both cell types, c-Fos and Fra-1 proteins increased after EGF treatment, but differences in the induction of Jun proteins were noted, with an increase of c-Jun in hepatocytes and an increase of JunB in 7777 cells. In both cell types, activation of AP-1 DNA binding activity by EGF was accompanied by the recruitment of Fra-1 into AP-1, detected earlier in 7777 cells than in hepatocytes, and with the transient appearance of c-Fos in 7777 cells only. Finally, EGF activated AP-1-dependent transcription in 7777 cells but not in hepatocytes. These data indicate important differences in the functional activity of AP-1 in transformed hepatocytes.

Animals↗

PubMed2004

Ethanol impairs insulin's actions through phosphatidylinositol 3-kinase.

Insulin plays an important role in cell metabolism and proliferation. In the present study, we examined the effect of ethanol on insulin actions such as glucose uptake, DNA synthesis, and c-Jun gene expression. Acute treatment with ethanol (200 mM) for 60 minutes inhibited insulin-stimulated 2-deoxyglucose uptake by 50% in 3T3-L1 adipocytes. Insulin-induced DNA synthesis and c-Jun protein expression were also reduced by ethanol treatment in Rat-1 fibroblasts overexpressing normal human insulin receptor. Ethanol has no effect on tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1. However, association of the insulin receptor and IRS-1 with the Src homology 2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) was reduced by ethanol. Pretreatment with the antidiabetic drug troglitazone, an insulin-sensitizer, reversed ethanol's inhibition. These results suggest that ethanol specifically inhibits the association of the insulin receptor and IRS-1 with the p85 subunit of PI3-kinase, which is required for increased glucose uptake, DNA synthesis, and c-Jun expression by insulin.

3T3 Cells↗

PubMed2006

Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo: an implication for gene therapy targeting congenital protein deficiencies.

Maintenance of high-level transgene expression is the main challenge in current gene therapy. Although the cytomegalovirus (CMV) promoter/enhancer or its derivative the CAG promoter has been harnessed in current gene therapy vectors, transgene expression by these vectors is often transient and remains at suboptimal levels due to undefined mechanisms, possibly including the shortage of transcriptional machinery. To overcome this drawback, we designed a novel transcriptional control system, designated here as transcription factor-supercharging promoter system, in which transgene expression is regulated by the positive feedback circuit consisting of cis- and trans-acting elements of gene expression machinery. Among combinations of these elements, a plasmid composed of a target gene expression cassette driven by the chimeric CMV promoter containing repetitive 12-O-tetradecanoylphorbol-13-acetate-responsive elements as cis-acting elements (CMV-TTT) and expression cassettes for c-Fos and c-Jun genes as trans-acting elements facilitated high and long-term (>10 months) expression of a transgene after its intramuscular electroporation-mediated delivery in mice. Since human secretory alkaline phosphatase was used as a reporter, it was suggested that the immune evasion mechanism elicited by the CMV-TTT and/or c-Fos/ c-Jun expression also contributed to the sustained expression in mice. Our strategy may open a new avenue for a gene therapy that involves lifelong supplementation of a deficient protein that could be targeted by the host's immune system.

Animals↗

PubMed1991

Inhibition of protein phosphatases by okadaic acid induces AP1 in human T cells.

To examine the role of protein phosphatases in T cell activation, Jurkat cells were treated with okadaic acid, an inhibitor of type 1 and 2A phosphatases, and nuclear extracts were examined for the presence of AP1 as a measure of early T cell activation. Okadaic acid was found to be a potent inducer of AP1. In contrast to phorbol esters such as phorbol myristate acetate (PMA), the induction of AP1 by okadaic acid occurs predominantly by transcriptional activation of the jun and fos family of proto-oncogenes. Surprisingly, while the addition of phytohemagglutinin further enhanced the induction of AP1, the addition of PMA inhibited it. Okadaic acid treatment was found to dramatically increase mRNA transcripts of the jun family of proto-oncogenes including c-jun, junD, and junB and to a lesser extent the fos family including c-fos and fra-1. By comparison, PMA is a very inefficient inducer of the jun gene family in Jurkat cells. Similar to its effect on the induction of AP1 by okadaic acid, PMA inhibits the induction of c-jun mRNA by okadaic acid. Transfection of c-jun promoter constructs confirmed the marked difference between PMA and okadaic acid in inducing c-jun transcription. The induction of AP1 by okadaic acid suggests that protein phosphatases 1 and 2A (PP1 and PP2A) may be involved in T cell activation as important negative regulators of the transcription factor AP1.

Base Sequence↗

PubMed1993

Serum modulates mast cell responses to IgE antigen stimulation.

Serum induces the expression of the fos and jun gene families, which encode the transcription factor AP-1. Since we previously found that activation of mast cells by IgE-antigen (Ag) induces the mRNA accumulation of c-fos, c-jun, junB and junD proto-oncogenes, we were prompted to investigate whether serum could affect such accumulation in these cells. In addition, we investigated whether serum could modulate inhibition of DNA synthesis in immunologically stimulated mast cells. Mast cells, which were cultured in the presence of fetal calf serum (FCS), were characterized by a high proliferation rate and high accumulation of the mRNA of c-fos, junB and junD proto-oncogenes. After sustained FCS deprivation both DNA synthesis and the level of c-fos mRNA were significantly decreased, as expected, whereas the level of c-jun, junB and junD mRNA were not affected. As opposed to mast cells which were cultured in the presence of FCS, immunological stimulation of FCS-deprived cells resulted in DNA synthesis inhibition and an increase in c-fos expression. The results also show that the level of c-fos mRNA was increased by either IgE-Ag or FCS up to a similar level, while these two triggers could not act synergistically to enhance this expression further. Thus, changes in DNA synthesis, induced by FCS, block the ability of the immunological challenge to inhibit mast cell growth and to enhance c-fos mRNA accumulation.

Animals↗

PubMed1995

UV light as a footprinting agent: modulation of UV-induced DNA damage by transcription factors bound at the promoters of three human genes.

Protein-DNA interactions in mammalian cells can be analyzed at the nucleotide level of resolution by genomic sequencing techniques. The most sensitive genomic sequencing method uses the ligation-mediated polymerase chain reaction (LMPCR) for signal amplification to detect the positions of DNA modifications or strand breaks. Various probing methods are compatible with LMPCR, but dimethyl sulfate footprinting has most commonly been used. Here, we have examined the suitability of ultraviolet (UV) light as an in vivo footprinting agent to detect a wide variety of protein-DNA contacts. The distribution of the two major types of UV-induced DNA photoproducts (cyclobutane pyrimidine dimers and (6-4) photo-products) has been examined along the promoter sequences of three human genes. A comparison of UV-irradiated naked DNA and UV-irradiated cells reveals differences in the UV damage spectrum for both types of photoproducts. These differences can be either decreases or dramatic increases of photoproduct frequency. At the promoter of the c-jun gene, these differences ("photofootprints") co-localize with binding sites for two AP-1-like transcription factors, a CCAAT box binding protein, an SP-1 sequence, an NF-jun sequence, a related to serum response factor (RSRF) binding site and a sequence bound by an unknown factor. In the promoter of the gene coding for proliferating cell nuclear antigen (PCNA), photofootprints were seen at two SP-1 like sequences and two CCAAT boxes. The c-fos promoter is characterized by photofootprints at the serum response element (SRE), at the adjacent binding site for ternary complex factor (TCF), at an AP-1 site and at a binding site for a growth factor inducible protein (SIF). Photofootprints may be signatures of specific transcription factors or families of related factors since we noticed that the photofootprints seen at several common factor binding sites were similar or identical when the same site was analyzed in different genes. Photofootprints were not seen at sequences distant from transcription factor binding sites. A comparison of our UV photofootprinting data with data from experiments using other probing strategies shows that UV light has the potential to reveal all protein-DNA interactions provided there is a dipyrimidine sequence on either DNA strand within a factor binding site. The simplicity of using this probing agent together with its specificity for detecting a large variety of different factors should make UV light a generally useful tool for in vivo footprinting studies.

Base Sequence↗

PubMed1994

Transcriptional regulation of myelin associated glycoprotein gene expression by cyclic AMP.

The treatment of rat glioma C6 cells with 10 microM isoproterenol (Ipt) for 4 days upregulated the expression of the myelin-associated glycoprotein (MAG) gene by approximately 55-fold over the control value. The constant presence of Ipt in the medium was required for the maximal upregulation, as time-restricted exposures to the drug produced only partial, or no upregulation of the gene. No difference in the MAG mRNA stability could be detected in Ipt-treated vs untreated cells indicating that the drug upregulates the MAG gene at transcriptional level. Serum (FCS) strongly attenuated the response of the MAG gene to Ipt. The stimulatory effect of Ipt was profoundly reduced by spermine and H-89, indicating that protein kinase A-dependent protein phosphorylation is involved in the MAG gene activation. Within 30 min after Ipt administration, the c-fos gene was upregulated by 10-fold, and thereafter, its message level decreased and stabilized at approximately 3-fold over control. In contrast, the c-jun gene was downregulated to approximately 20% of control within 30 min after Ipt administration. Subsequently, its message level rose and fell once again within 12 h to approximately half of control, and returned to control level within 72 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Transforming growth factor-beta inhibits lipopolysaccharide-stimulated expression of inflammatory cytokines in mouse macrophages through downregulation of activation protein 1 and CD14 receptor expression.

The septic shock that occurs in gram-negative infections is caused by a cascade of inflammatory cytokines. Several studies showed that transforming growth factor-beta1 (TGF-beta1) inhibits this septic shock through suppression of expression of the lipopolysaccharide (LPS)-induced inflammatory cytokines. In this study, we investigated whether TGF-beta1 inhibition of LPS-induced expression of inflammatory cytokines in the septic shock results from downregulation of LPS-stimulated expression of CD14, an LPS receptor. TGF-beta1 markedly inhibited LPS stimulation of CD14 mRNA and protein levels in mouse macrophages. LPS-stimulated expression of CD14 was dramatically inhibited by addition of antisense, but not sense, c-fos and c-jun oligonucleotides. Since TGF-beta1 pretreatment inhibited LPS-stimulated expression of c-fos and c-jun genes and also the binding of nuclear proteins to the consensus sequence of the binding site for activation protein 1 (AP-1), a heterodimer of c-Fos and c-Jun, in the cells, TGF-beta1 inhibition of CD14 expression may be a consequence of downregulation of AP-1. LPS-stimulated expression of interleukin-1beta and tumor necrosis factor alpha genes in the cells was inhibited by addition of CD14 antisense oligonucleotide. Also, TGF-beta1 inhibited the LPS-stimulated production of both inflammatory cytokines by the macrophages. In addition, TGF-beta1 inhibited expression of the two cytokines in several organs of mice receiving LPS. Thus, our results suggest that TGF-beta1 inhibition of LPS-stimulated inflammatory responses resulted from downregulation of CD14 and also may be a possible mechanism of TGF-beta1 inhibition of LPS-induced septic shock.

Animals↗

PubMed1992

Expression of ileal glucagon and peptide tyrosine-tyrosine genes. Response to inhibition of polyamine synthesis in the presence of massive small-bowel resection.

Massive small-bowel resection results in a marked adaptive response in the residual terminal ileum. Increased polyamine synthesis is a necessary component of this response. The ileal L-cell-derived peptides enteroglucagon and peptide tyrosine tyrosine (PYY) have been implicated as humoral mediators of this response. We have previously reported a rapid and sustained increase in glucagon mRNA concentrations after massive small-bowel resection. In this study using an inhibitor of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase, we have demonstrated that the response of the glucagon and PYY genes to massive small-bowel resection is dependent on polyamine biosynthesis. In addition, we have examined the response of both the ornithine decarboxylase and c-jun genes in this model of intestinal adaptation.

Animals↗

PubMed1994

Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase.

Tumor necrosis factor alpha (TNF alpha) has multiple biological functions including the prolonged activation of the collagenase and c-jun genes, which are regulated via their AP-1 binding sites. We show that incubating human fibroblasts with TNF alpha induces prolonged activation of JNK, the c-Jun kinase, which phosphorylates the transactivation domain of c-Jun. Furthermore, an immune complex kinase assay specifically demonstrates that TNF alpha stimulates the activity of JNK1, the recently described predominant form of JNK. TNF alpha also produces a small and transient increase in extracellular signal-regulated kinase (ERK) activity and no measured increase in Raf-1 kinase activity. On the other hand, epidermal growth factor causes a prolonged activation of Raf-1 kinase and ERK activity and a smaller, more transient activation of JNK, whereas the phorbol ester phorbol 12-myristate 13-acetate causes a small stimulation of Raf-1 kinase and a pronounced stimulation of ERK activity. The activation of JNK by TNF alpha does not correlate with Raf-1 or ERK activity. The kinetics of Raf-1, ERK, and JNK induction by epidermal growth factor, phorbol 12-myristate 13-acetate, or TNF alpha indicate distinct mechanisms of activation in human fibroblasts.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1995

Apoptosis and c-jun induction by cisplatin in a human melanoma cell line and a drug-resistant daughter cell line.

Cisplatin resistance was developed in the human melanoma cell line RPMI8322 by repeated short-term exposures to cisplatin. The most resistant daughter cell line, RPMI8322/CDDP-300, was 4-fold resistant to cisplatin, and partially cross-resistant to carboplatin, melphalan and UV, but not to BCNU. RPMI8322/CDDP-300 cells showed less apoptosis after cisplatin than the parental cells. The cisplatin resistance was not paralleled by a similar reduction in cellular cisplatin accumulation or DNA cross-links in RPMI8322/CDDP-300 cells, and these cells exhibited no increase in cellular glutathione or in mRNA encoding the DNA excision repair protein ERCC1 and XPB. Induction of c-jun mRNA by cisplatin was considerably lower in RPMI8322/CDDP-300 cells than in RPMI8322 cells, consistent with the possibility that c-jun induction may be involved in a pathway that triggers apoptosis after exposure to DNA damaging agents. However, c-jun induction is not necessary for apoptosis, since cisplatin also induced apoptosis in A14 rat embryo fibroblasts, cells in which the c-jun gene is deleted.

Animals↗

PubMed1990

Cooperation of v-jun and v-erbB oncogenes in embryo fibroblast transformation in vitro and in vivo.

Retroviral vectors carrying either the v-jun and v-erbB sequences or the v-jun gene linked to the neomycin resistance gene were constructed on the basis of the structural genome organization of avian erythroblastosis virus (AEV). These viruses, called JB and JN, respectively, were rescued as Rous-associated virus-1 pseudotypes, and they were shown to successfully transform chicken embryo fibroblasts in vitro. However, in agar, colonies developed from JB-infected fibroblasts were three to five times larger than those obtained after infection with JN or with AEV Pst124 carrying only a functional v-erbB gene. In vivo, on chorioallantoic membrane (CAM) assays, JB produced fibrosarcomas that were more rapidly growing and much larger than those induced by JN or AEV Pst124. Moreover, in chickens infected in ovo with JB, multiple fibrosarcomas arose in different organs a few days after birth, whereas no tumor could be detected in parallel experiments in either JN- or AEV Pst124-infected animals. These results demonstrate that in embryo fibroblast cells, v-jun and v-erbB can act synergistically to enhance the transformation potential of either oncogene alone both in vitro and in vivo.

Alpharetrovirus↗

PubMed1995

Subtotal but not unilateral nephrectomy induces hyperplasia and protooncogene expression.

It is generally accepted that renal compensatory growth after unilateral nephrectomy (Uni) is due to prominent hypertrophy with no involvement of protooncogenes. Neither the balance between hypertrophy and hyperplasia nor the expression of the early-growth-related genes has been studied after subtotal nephrectomy (Nx). The occurrence of cystic tubular dilatations after Nx may suggest an excessive cell proliferation in this model. We measured DNA, RNA, and protein content, number of nuclei per tubular section, as well as c-fos, c-jun, c-myc, c-H-ras, c-sis, and c-erb-B2 protooncogene expression in kidneys taken at time of surgery and 2, 7, and 14 days after sham operation (control rats), Uni, or Nx. After Uni, hyperplasia was greater than expected (+79% for DNA at day 14) and was associated with moderate hypertrophy (+11% for protein/DNA ratio). After Nx, compensatory growth was due only to hyperplasia (+117% for DNA at day 14), with unchanged protein/DNA ratio (vs. Uni, P < 0.02). The greater hyperplasia after Nx was confirmed by nuclei counting. The protooncogene mRNA expression was constantly absent in control and Uni rats, whereas that of c-fos and c-jun genes was detected in Nx rats at day 14 with a 2- to 12-fold increment. The c-fos and c-jun protein levels were also increased at that time in Nx rats. This suggests the following: 1) the cellular events following Uni and Nx are not the same, and 2) the late protooncogene expression in Nx exclusively could favor a particular type of cell proliferation possibly more related with cystic formation than with actual compensatory growth.

Adaptation, Physiological↗