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Biomedical subjects

A H Miller

Publications and source records attributed to A H Miller.

At least 19 recordsLinked to original sources
PubMed1997

Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection.

Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-gamma, TNF, IL-1alpha, and IL-6 were shown to be increased, but IL-1beta was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-gamma, TNF, and IL-6 responses were dramatic with peak levels reaching >150-10,000 pg/ml at 32-40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

Adrenocorticotropic Hormone↗
PubMed1996

Stress-induced changes in blood leukocyte distribution. Role of adrenal steroid hormones.

The numbers and proportions of leukocytes in the blood provide an important representation of the state of activation of the immune system, and of the pattern of distribution of immune cells in the body. We have shown previously that acute stress induces large, rapid, and reversible changes in the distribution of peripheral blood leukocyte subpopulations in the rat. The studies described here specifically investigate the role played by adrenal steroid hormones in mediating stress-induced changes in blood leukocyte distribution. Since adrenal steroids act at two distinct receptor subtypes that show a heterogeneity of expression in immune cells and tissues, the role played by each subtype in mediating changes in leukocyte distribution is also investigated. Cyanoketone, a corticosterone (CORT) synthesis inhibitor, significantly reduced the decrease in lymphocyte numbers observed during stress and significantly enhanced the increase in neutrophil numbers observed after the cessation of stress. Acute administration of aldosterone (a specific type I adrenal steroid receptor agonist) to adrenalectomized animals did not have a significant effect on blood leukocyte numbers. In contrast, acute administration of CORT (the endogenous type I and type II receptor agonist), or RU28362 (a specific type II receptor agonist), to adrenalectomized animals produced changes in leukocyte distribution that were similar to those observed in intact animals during stress. These results suggest that CORT, acting at the type II adrenal steroid receptor, is a major mediator of the stress-induced changes in blood lymphocyte and monocyte distribution.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Chronic social stress produces reductions in available splenic type II corticosteroid receptor binding and plasma corticosteroid binding globulin levels.

Adult male and female rats were housed for 2 weeks in a Visible Burrow System resulting in the development of strong dominant-subordinate relationships among the male rats. Neuroendocrine measures indicated that the subordinate rats, and to a lesser extent dominant rats, experienced chronic HPA axis hyperstimulation during the 2 week experience. This paper focuses on the consequences of this chronic social stress on cytosolic type II corticosteroid receptor binding in the spleen. In the first study, rats were adrenalectomized 18 h prior to sacrifice in order to measure total cellular receptor protein levels in each animal. In spite of the severity of the social stress, there was no decrease in splenic type II corticosteroid receptor binding levels in these short-term adrenalectomized animals. In the second study, rats were left adrenal-intact. Corticosteroid receptor levels in these adrenal-intact animals reflect the level of receptors (available receptors) that were unoccupied by endogenous hormone at the time of sacrifice. Both subordinate and dominant rats had fewer available splenic type II receptors than control rats, suggesting that a greater proportion of receptors in subordinate and dominant rats were occupied and activated by endogenous hormone at the time of sacrifice than in control rats. The differences in available receptor levels were not a function of total plasma corticosterone levels at the time of sacrifice (mean corticosterone levels were the same for control and subordinate rats). Instead, the differences in available receptor levels may have been a function of plasma corticosteroid binding globulin (CBG) levels which regulate free corticosterone levels. There was a large reduction in plasma CBG levels of subordinate (-70%) and dominant (-40%) rats relative to control rats, and there was a significant correlation between plasma CBG level and available type II receptors in the spleen. These results suggest that a decrease in CBG levels as a result of chronic social stress led to greater access of free corticosterone hormone to type II receptors in the spleen than is typically present in rats under basal or acute stress conditions. This result illustrates one mechanism by which chronic stress may have a greater impact than acute stress on splenic immune function.

Animals↗
PubMed1995

Effects of stress on immune cell distribution. Dynamics and hormonal mechanisms.

Immune cell trafficking is crucial to the performance of the surveillance as well as effector functions of the immune system. Because immune cells travel between tissues through the bloodstream, the numbers and proportions of leukocytes in the circulation provide an important representation of the state of leukocyte distribution in the body. The studies described here examine significant and selective changes in numbers and percentages of peripheral blood leukocyte subpopulations in the rat. These changes were rapidly induced under conditions of mild acute stress. Stress-induced increases in plasma corticosterone were accompanied by a significant decrease in numbers and percentages of lymphocytes, and by an increase in numbers and percentages of neutrophils. flow cytometric analysis revealed that B cell, NK cell, and monocyte numbers showed a greater stress-induced decrease than did T cells. All stress-induced changes were observed during the light (inactive) as well as the dark (active) period of the animal's diurnal cycle. Importantly, the stress-induced changes in leukocyte numbers and percentages were rapidly reversed upon the cessation of stress. Furthermore, the effects of stress were largely dependent on adrenal hormones, because the magnitude of the stress-induced changes was significantly reduced in adrenalectomized animals. Moreover, administration of corticosterone to adrenalectomized animals resulted in a close replication of stress-induced changes observed in adrenal-intact animals. These results suggest that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments. Such a redistribution may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge.

Adrenal Glands↗
PubMed1995

Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids.

Interleukin 12 (IL-12) doses in excess of 100 ng/d have been shown to induce profound immunotoxicities in mice infected with lymphocytic choriomeningitis virus (LCMV). These immunotoxicities are characterized by almost complete inhibition of virus-induced CD8+ T cell expansion and CTL activation, and up to 2 log increases in viral replication. They are accompanied by induction of serum tumor necrosis factor (TNF). The studies presented here were undertaken to characterize mechanisms for the IL-12-induced toxicities and to examine expression and function of TNF in this context. Several physiological changes were induced in IL-12-treated uninfected and dramatically elevated in IL-12-treated virus-infected mice. IL-12 induced (a) decreases in body weights, > 10% in uninfected and > 20% in LCMV-infected mice; (b) elevation of circulating glucocorticoid levels to > 10 micrograms/dl in uninfected and > 20 micrograms/dl in infected mice; and (c) decreases in thymic mass, > 30% in uninfected and up to 95% in infected mice. These changes are known to be associated with circulating TNF. Northern blot and in situ hybridization analyses demonstrated that IL-12 induced TNF-alpha expression and that LCMV infection synergized with IL-12 for induction of this factor. Antibodies neutralizing TNF reversed all of the IL-12-induced toxicities in LCMV-infected mice including the immunotoxicities against CD8+ T cells and anti-viral defenses. The TNF-mediated immunotoxicities appeared to result from an induced cellular sensitivity to the factor, as splenic leukocytes and CD8+ T cell subsets isolated from LCMV-infected mice were more sensitive to TNF-mediated cytotoxicity in culture than were equivalent populations prepared from uninfected mice. Experiments with the glucocorticoid type II receptor antagonist, RU486, demonstrated that endogenous glucocorticoids were secondary intermediaries in IL-12-induced thymic atrophy. Studies in IL-2-deficient mice showed that the synergism was dependent upon endogenous IL-2. The results delineate a unique mechanism of TNF-mediated toxicity. In addition, they have significant implications concerning potential detrimental consequences of in vivo TNF induction and of IL-12 administration for protective anti-viral responses.

Animals↗
PubMed1995

Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats.

Sprague Dawley (SD), Fischer 344 (F344), and Lewis (LEW) rats are used in a wide variety of laboratory studies. Compared to SD and LEW rats, F344 rats show significantly greater corticosterone secretion in response to stress, or to immune challenge. These strain differences in hypothalamic-pituitary-adrenal (HPA) axis responsivity have been the basis for many comparative studies investigating immunological and behavioural differences between the three strains. However, the effects of these strain differences in HPA axis responsivity have not been investigated at the level of adrenal steroid receptor activation in target tissues. The present study demonstrates that compared to SD and LEW rats, F344 rats exhibited a greater magnitude of Type II adrenal steroid receptor activation in brain tissues during stress. In contrast, Type II receptor activation in immune tissues of F344 rats following stress was similar to that of SD rats. Importantly, LEW rats exhibited the lowest magnitude of activation of Type II receptors in immune tissues during stress. No differences were observed between strains in the extent of stress-induced Type I adrenal steroid receptor activation. The observed differences between strains in corticosteroid-binding globulin (CBG) levels in plasma, pituitary, and immune tissue may mediate the differential access of corticosterone to neural versus immune tissues. These results indicate that strain differences in corticosterone secretion are manifested by differences in Type II receptor activation in neural as well as immune tissues. Moreover, they suggest that increased access of corticosterone to adrenal steroid receptors in brain areas of F344 rats may contribute to behavioural differences between strains, whereas decreased access of hormone to receptors in immune tissues of LEW rats may contribute to strain differences in susceptibility to autoimmune disease.

Adrenal Glands↗
PubMed1995

Natural killer cell activity in major depression: a prospective study of the in vivo effects of desmethylimipramine treatment.

To evaluate NK activity changes associated with both the diagnosis of major depressive disorder (MDD) and the in vivo treatment of MDD with the tricyclic antidepressant desmethylimipramine (DMI), 15 MDD outpatients (11 females, four males) and eight controls (six females, two males) were evaluated prospectively at intake and after an average of 12 weeks of standardized DMI treatment. Plasma DMI concentrations at follow-up and severity of depression using the Extracted Hamilton Depression Rating Scale (EH) score at both intake and follow-up were also evaluated. At intake, NK activity was significantly higher in depressed patients compared to controls (P < 0.0001) while at follow-up NK activity was not different between the two groups. NK activity decreased from intake to follow-up in depressed patients but not in controls. A second analysis of NK activity was performed by dividing depressed patients into responders and nonresponders (EH > or = 8 at follow-up). At intake, there was no difference between responders and nonresponders while at follow-up NK activity was lower in nonresponders (P < 0.0001). Only nonresponders had a significant decrease in NK activity from intake to follow-up. No correlation was found between DMI blood level and NK activity, and no difference in NK activity was present between those with the highest and lowest DMI blood levels. Although it is apparent that both MDD and its treatment influenced NK activity in this study, it is unclear whether the decrease in NK activity in nonresponding patients was a function of persistent depressed mood and/or DMI treatment.

Adult↗
PubMed1995

Glucocorticoid receptors in depression.

During major depression, dysfunction of limbic structures resulting in hypersecretion of corticotropin-releasing factor (CRF) is believed to cause the well-known hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this disorder. Nonsuppression of the HPA axis by dexamethasone in depressed patients suggest that this increased CRF secretion may be due, at least in part, to altered feedback inhibition by glucocorticoids. Because glucocorticoid-induced feedback inhibition of the HPA axis is mediated by glucocorticoid receptors (GRs) in the brain and pituitary, the possibility that depression is associated with a primary alteration in GRs number and/or function has been an important consideration regarding the pathophysiology of the depressive disorders. Nevertheless, studies investigating GRs kinetics in depressed patients have been inconsistent. In some studies, decreased GRs number in depressed patients has been observed; others have obtained discordant results. The inconsistency of results may be due to a number of factors, including patient heterogeneity, the cell populations sampled, and the methods used to determine receptors number. Fewer studies have investigated the functional sensitivity of cells to the inhibitory effects of glucocorticoids, but they have been more consistent, showing increased resistance of cells from depressed patients to the inhibitory effects of glucocorticoids on immune function. In view of intriguing data indicating monoamine regulation of GR number and function in a hormone independent fashion along with the well-known effects of glucocorticoids on behavior, further scrutiny of the role of GR in depression and its treatment is warranted.

Antidepressive Agents↗
PubMed1994

Diurnal and acute stress-induced changes in distribution of peripheral blood leukocyte subpopulations.

In this study, we examined hormonal regulation of the distribution profiles of leukocyte subpopulations in the peripheral blood of rats. Flow cytometric analysis revealed significant and selective changes in the numbers and the percentages of peripheral blood leukocyte subpopulations which were a function of diurnal variations in hormone secretion and hormonal changes induced by acute stress. Changes in numbers and percentages of leukocyte subpopulations, which varied with time of day, were similar to changes observed under stress conditions. At the beginning of the rat's active period, and after 1 h of restraint stress, there was a significant reduction in numbers of leukocytes and lymphocytes. This reduction was primarily accounted for by a decrease in numbers of B cells, natural killer cells, monocytes (diurnal study), and helper T cells (diurnal study). There was also a significant decrease in the percentage of lymphocytes which was mirrored by an increase in the percentage of neutrophils in the peripheral blood. Peripheral blood leukocyte numbers were inversely related to plasma corticosterone levels. These results suggest that the endocrine system plays a role in the regulation of immune cell turnover and/or redistribution between immune compartments under conditions of normal daily experiences, namely, the diurnal cycle, and mild acute stress. They also suggest that these effects are selective for certain subpopulations of leukocytes.

Acute Disease↗
PubMed1994

Lack of association between cortisol hypersecretion and nonsuppression on the DST in patients with Alzheimer's disease.

Among 23 patients with Alzheimer's disease, 11 (48%) exhibited cortisol hypersecretion (> or = 11.8 micrograms/dl) and nine (39%) displayed cortisol nonsuppression on the dexamethasone suppression test. Only four patients exhibited both neuroendocrine abnormalities, demonstrating a lack of association between these two neuroendocrine disturbances of over 50%. Twenty-two of the 23 patients were studied for 4 1/2 years, and 14 died during that period. Six of the eight surviving patients exhibited cortisol hypersecretion without cortisol nonsuppression.

Aged↗
PubMed1994

Effects of selective type I and II adrenal steroid agonists on immune cell distribution.

Adrenal steroids exert their effects through two distinct adrenal steroid receptor subtypes; the high affinity type I, or mineralocorticoid, receptor and the lower affinity type II, or glucocorticoid, receptor. Adrenal steroids have well known effects on immune cell distribution, and although both type I and II receptors are expressed in immune cells and tissues, few data exist on the relative effects mediated through these two receptor subtypes. Accordingly, we administered selective type I and II adrenal steroid receptor agonists to young adult male Sprague-Dawley rats for 7 days and then measured immune cell distribution in the peripheral blood and spleen. Results were compared with those of similar studies using the naturally occurring glucocorticoid of the rat, corticosterone, which binds both type I and II receptors. The majority of the well characterized effects of adrenal steroids on peripheral blood immune cells (increased neutrophils and decreased lymphocytes and monocytes) were reproduced by the type II receptor agonist, RU28362. RU28362 decreased the numbers of all lymphocyte subsets [T-cells, B-cells, and natural killer (NK) cells] to very low absolute levels. The largest relative decrease (i.e. in percentage) was seen in B-cells, whereas NK cells exhibited the least relative decrease and actually showed a 2-fold increase in relative percentage during RU28362 treatment. Similar to RU28362, the type I receptor agonist, aldosterone, significantly reduced the number of lymphocytes and monocytes. In contrast to RU28362, however, aldosterone significantly decreased the number of neutrophils. Moreover, aldosterone decreased the number of T-helper cells and NK cells, while having no effect on the number of B-cells or T-suppressor/cytotoxic cells. Corticosterone at physiologically relevant concentrations had potent effects on immune cell distribution, which were indistinguishable from those of the type II receptor agonist, RU28362. Taken together, these results indicate that effects of adrenal steroids on immune cell distribution are dependent on the receptor subtype involved as well as the specific cell type targeted. These factors allow for varied and complex effects of adrenal steroids on the immune system under physiological conditions.

Aldosterone↗
PubMed1993

Diurnal differences in basal and acute stress levels of type I and type II adrenal steroid receptor activation in neural and immune tissues.

To examine diurnal differences in the proportions of receptors that were occupied and activated by basal and stress levels of corticosterone, we measured available type I (mineralocorticoid) and type II (glucocorticoid) adrenal steroid receptor levels in brain, pituitary, and immune tissues of unstressed and acutely stressed rats at the times of day when basal corticosterone secretion was at its trough [morning (AM)] and peak [evening (PM)]. In general, the estimated adrenal steroid receptor activation was greater in brain than in pituitary or immune tissue, and within a particular tissue, there was a greater degree of estimated activation of the adrenal steroid high affinity type I receptor than of the type II receptor. There was a greater activation of brain type II receptors by basal corticosterone in the PM (30-35%) than the AM (5-15%). As acute stress produced similar levels of receptor activation at both times of day (45-50%), the net change in type II receptor activation in the brain after acute stress was much smaller in the PM than in the AM. This suggests that there may be diurnal differences in the role of type II receptors in corticosterone negative feedback on the hypothalamic-pituitary-adrenal axis. In immune tissues, type II receptor activation by acute stress was especially heterogeneous, depending on both the immune compartment and the time of day, suggesting that these are important factors contributing to a differential impact of corticosterone on immune responses during acute stress. Taken together our results suggest that the tonic and phasic influences of corticosterone on target tissue responses very not only with the diurnal and stress secretion patterns of corticosterone, but also with target tissue factors, such as type I and type II receptor expression and hormone bioavailability. All of these factors contribute to considerable selectivity of action for the systemic hormone corticosterone.

Adrenalectomy↗
PubMed1993

Differential expression of type I adrenal steroid receptors in immune tissues is associated with tissue-specific regulation of type II receptors by aldosterone.

We examined the influence of the type I adrenal steroid receptor agonist, aldosterone, on type II adrenal steroid receptor binding in the rat spleen and thymus after adrenalectomy. In the spleen, adrenalectomy was associated with a significant up-regulation of type II receptors, which was blocked by the concurrent administration of aldosterone (1 microgram/h) via sc osmotic minipumps. Neither adrenalectomy nor aldosterone treatment altered type II receptor binding in the thymus. Despite high doses of aldosterone (10 micrograms/h), which resulted in supra-physiological blood concentrations of this hormone, there was no evidence of type II receptor decreases in spleen or thymus below receptor levels found in sham-adrenalectomized rats. The effect of aldosterone on type II receptor binding appeared to be mediated by the type I receptor, since there was no aldosterone effect on the thymus, which did not exhibit detectable levels of type I receptor binding. Moreover, there was no evidence that aldosterone competed for the type II receptor in vivo or in vitro as determined by measurements of the type II receptor dissociation constant in the spleen of adrenalectomized, aldosterone-treated animals. Since selective activation of the type I receptor occurs in the spleen under physiological conditions, these results indicate that type I receptors may play a tonic inhibitory role in type II receptor expression in immune cells which express both receptor subtypes and reside in this tissue. Furthermore, the findings suggest that there may be different mechanisms involved in the up-regulation vs. the down-regulation of type II adrenal steroid receptors, and effects mediated solely via the type I adrenal steroid receptor appear only to influence the former process.

Adrenalectomy↗
PubMed1993

Depression, adrenal steroids, and the immune system.

During the past decade, over 30 studies have examined the immune system in depression. While a number of investigators have reported depression-related alterations in peripheral blood immune cell number and function, many researchers have been unable to replicate these findings. The relationship between depression and the immune system has turned out to be much more complex than was initially anticipated. Factors which have complicated the interpretation of the research include the heterogeneity of depressed patients, the variability of immune assays, and the clinical relevance of these assays. In this review we conclude that alterations in the immune system do not appear to be a specific or reproducible biological correlate of depression but may occur in association with other variables which characterize depressed patients including age, sex and severity of depression. Conceptual frameworks for future research on the immune system and depression are discussed and include: (i) depression as a cofactor in the development, course and outcome of diseases involving the immune system; (ii) depression as a neuroimmunological disease; and (iii) depression as a model for studying neuroendocrine-immune interactions in humans. In terms of this third line of research, patients with depression consistently have been shown to display abnormalities in the secretion of adrenal steroids, and new data is presented which indicates that adrenal steroids may play a much more complex role in the modulation of the immune response than has been previously appreciated.

Adrenal Cortex Hormones↗
PubMed1992

Adrenal steroid receptor activation in rat brain and pituitary following dexamethasone: implications for the dexamethasone suppression test.

The dexamethasone suppression test (DST) has been used extensively to evaluate feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis by adrenal steroids. Nevertheless, it remains unclear at what level of the HPA axis and through which adrenal steroid receptor subtype dexamethasone exerts its inhibitory effect. Because adrenal steroid receptor activation is an important prerequisite for dexamethasone to affect cellular function, HPA axis tissues that exhibit evidence of receptor activation following dexamethasone administration are likely site(s) of action for this synthetic hormone to inhibit HPA axis activity. Therefore, type-I and type-II adrenal steroid receptor activation was assessed in the pituitary, hypothalamus, and hippocampus of intact and adrenalectomized rats after overnight exposure to various oral doses of dexamethasone. Results with dexamethasone were compared to similar studies using corticosterone, the endogenous glucocorticoid of the rat. All dexamethasone doses led to significant type-II receptor activation in the pituitary, whereas only an exceedingly high dexamethasone dose activated type-II receptors in the hippocampus and hypothalamus. Dexamethasone had little effect on type I receptors in any tissue at any dose. In contrast, corticosterone significantly activated type-I receptors in all tissues, whereas it activated type-II receptors in the brain and not the pituitary at physiological concentrations. Because dexamethasone activated pituitary type-II receptors at blood concentrations that did not activate type-II receptors in the brain, these results suggest that the DST in humans may primarily be a measure of type-II adrenal steroid receptor feedback inhibition at the level of the pituitary.

Adrenalectomy↗
PubMed1992

Dissociation of nuclear events on p21 RAS transformation of FDC-P1 myeloid cells: c-jun/AP-1 expression versus c-myc transcription.

We have previously reported transformation to growth factor-independent proliferation in the interleukin-3 (IL-3)-dependent cell line FDC-P1 by high-level expression of the valine 12 Harvey RAS oncogene, following from a nonautocrine mechanism. The present study was undertaken to examine nuclear tertiary messenger, transcriptional response gene expression to deduce the intracellular signaling pathways responsible for this autonomous proliferation. We confirmed other reports that transformed p21RAS-expressing cells constitutively express the transcription factor complex jun/AP-1, in this case resulting from the ongoing expression of the c-jun and c-fos genes in the absence of IL-3. However, the ongoing growth factor independent expression of c-myc by a transcriptional mechanism in FDC-P1 cells expressing p21 RAS cannot be explained by intracellular signaling in the jun/AP-1 (protein kinase C) pathway. This conclusion derives from the observation that c-jun expression mediated via protein kinase C activation with phorbol ester (12-0-tetra decanoylphorbol-13-acetate, TPA) treatment does not lead to c-myc expression in parent FDC-P1 cells. On the contrary, FDC-P1 cells stably transfected with a c-myc gene controlled under the influence of a metallothionein IIA promoter (containing the TPA-responsive element [TRE]) express the transfected MTIIA-c-myc and downregulate the endogenous c-myc in response to protein kinase C activation with TPA. Further, nuclear proteins derived from cells expressing p21 RAS, which bind specifically to the purified c-myc P2 promoter, are not competed in their binding to the motif-rich P2 element by AP-1 oligonucleotide. Therefore, expression of the Harvey RAS oncogene in FDC-P1 myeloid cells leads to at least two pathways of cytoplasmic signaling. One pathway involves protein kinase C and c-jun/AP-1, but another pathway that is protein kinase C-independent appears to mediate c-myc transcription.

Cell Line↗