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Biomedical subjects

Shigetake Sasayama

Publications and source records attributed to Shigetake Sasayama.

At least 37 records · Page 2Linked to original sources
PubMed2002

Thrombosis increases circulatory hepatocyte growth factor by degranulation of mast cells.

BACKGROUND: Plasma concentrations of hepatocyte growth factor (HGF), a powerful angiogenic growth factor inducible by heparin, increase in thrombus-associated disorders such as myocardial infarction and unstable angina. The mechanism of this thrombus-associated HGF release, however, is unknown. METHODS AND RESULTS: Wistar rats received through the tail vein (1) normal saline (NS), (2) 50 micro g of the mast cell-degranulating agent CP48/80, or (3) 1000 U/kg heparin. Blood samples were collected at 10 minutes or 30 minutes after the injections, or from untreated rats, for measurements of HGF. The same experiments were performed in mast cell-deficient white spotting (Ws) rats. Ws rats have a small deletion of the c-kit gene and are deficient in mast cells. Intravenous heparin immediately increased plasma HGF in both Wistar (38.02+/-2.08 ng/mL versus 1.11+/-0.70 ng/mL in untreated rats, P<0.0001) and Ws rats (36.39+/-4.15 ng/mL versus 0.66+/-0.18 ng/mL in NS-treated rats, P<0.0001). Injection of CP48/80 also increased plasma HGF in Wistar rats (9.12+/-1.11 ng/mL versus 0.65+/-0.24 ng/mL in NS group, P=0.004) but not in Ws rats (0.67+/-0.27 ng/mL versus 0.66+/-0.18 ng/mL in NS group, P=0.997). In a rat carotid artery microthrombus model, intra-arterial thrombus formation increased circulating HGF in Wistar rats (2.12+/-0.70 ng/mL versus sham 0.61+/-0.15 ng/mL in sham-operated Wistar rats, P=0.0064) but not in Ws rats (0.76+/-0.33 ng/mL versus 0.21+/-0.04 ng/mL in sham-operated Ws rats, P=0.29). In addition, in vitro stimulation of rat peritoneal mast cells with thrombin rapidly induced degranulation in a dose-dependent manner. CONCLUSIONS: These observations indicate that mast cell degranulation stimulated by thrombin is necessary for the rapid induction of plasma HGF in intravascular thrombus-associated disorders.

Animals↗
PubMed2002

Left ventricular pressure-volume relationship in a murine model of congestive heart failure due to acute viral myocarditis.

OBJECTIVES: This study, performed in a murine model of encephalomyocarditis virus myocarditis, used a new Millar 1.4F conductance-micromanometer system for the in vivo determination of the left ventricular (LV) pressure-volume relationship (PVR). BACKGROUND: Viral myocarditis is an important cause of congestive heart failure and may lead to dilated cardiomyopathy. However, the hemodynamic changes associated with its acute phase have not been analyzed in detail. METHODS: Four-week-old DBA/2 mice were inoculated with EMCV (day 0). Serial hemodynamic measurements, compared with uninfected control mice were made on days 0, 1, 3, 4, 5, 7, 9, 12, and 14. RESULTS: On day 1, the hearts of infected mice manifested enhanced contractile function, decreased LV compliance, and abnormal diastolic function with increased LV end-diastolic pressure (EDP). Mean stroke index, ejection fraction (EF), and cardiac index (CI) were significantly higher than in uninfected control mice (p < 0.05). Contractile function decreased from days 4 to 14. On day 7, when hemodynamic abnormalities consistent with heart failure culminated, end-diastolic volume (EDV), EDP, and EDPVR were significantly higher, and CI, EF, end-systolic pressure (ESP), and ESPVR significantly lower in the infected than in control mice. Heart rate remained comparable in both groups. Although heart failure receded between day 9 and day 14, ESPVR, ESP, and EF remained significantly depressed up to day 14, and EDV and EDP remained significantly higher. CONCLUSIONS: These hemodynamic data provide new insights into the pathophysiology of acute viral myocarditis and may be useful in the development of therapeutic interventions.

Animals↗
PubMed2002

Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats.

OBJECTIVES: We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling. BACKGROUND: Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated. METHODS: In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities. RESULTS: No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo. CONCLUSIONS: Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.

Animals↗
PubMed2002

Calcineurin-GATA-6 pathway is involved in smooth muscle-specific transcription.

Intracellular calcium is one of the important signals that initiates the myogenic program. The calcium-activated phosphatase calcineurin is necessary for the nuclear import of the nuclear factor of activated T cell (NFAT) family members, which interact with zinc finger GATA transcription factors. Whereas GATA-6 plays a role in the maintenance of the differentiated phenotype in vascular smooth muscle cells (VSMCs), it is unknown whether the calcineurin pathway is associated with GATA-6 and plays a role in the differentiation of VSMCs. The smooth muscle-myosin heavy chain (Sm-MHC) gene is a downstream target of GATA-6, and provides a highly specific marker for differentiated VSMCs. Using immunoprecipitation Western blotting, we showed that NFATc1 interacted with GATA-6. Consistent with this, NFATc1 further potentiated GATA-6-activated Sm-MHC transcription. Induction of VSMCs to the quiescent phenotype caused nuclear translocation of NFATc1. In differentiated VSMCs, blockage of calcineurin down-regulated the amount of GATA-6-DNA binding as well as the expression of Sm-MHC and its transcriptional activity. These findings demonstrate that the calcineurin pathway is associated with GATA-6 and is required for the maintenance of the differentiated phenotype in VSMCs.

Actins↗
PubMed2002

Amiodarone inhibits interleukin 6 production and attenuates myocardial injury induced by viral myocarditis in mice.

A recent study has shown that amiodarone inhibits the production of cytokines in vitro. This study was performed to examine the effects of amiodarone on survival, heart weight-to-body-weight ratio (HW/BW), myocardial lesions and cytokines production in a murine model of viral myocarditis induced by the encephalomyocarditis virus (EMCV). Four-week-old male DBA/2 mice were inoculated with the EMCV. To examine its effect on survival and HW/BW on day 14, mice were administered oral amiodarone (30 mg/kg) or the vehicle only once daily, starting 4 days before inoculation of the virus. The effects of amiodarone on histopathologic changes in myocardial lesions and myocardial cytokine production were studied in mice treated with amiodarone (10 mg/kg or 30 mg/kg) or vehicle, and killed day 7. The survival rate on day 14 was significantly higher in the amiodarone-treated mice than in the control mice. The HW/BW, histopathologic score of cellular infiltration and myocardial interleukin 6 concentration were significantly lower in the amiodarone-treated group than in the control group. Likewise, myocardial necrotic area was significantly smaller in the amiodarone group than in the control group. This study suggests that the beneficial effects of amiodarone in viral myocarditis may be mediated by decreasing interleukin 6 production in myocardial tissue.

Amiodarone↗
PubMed2002

Evidence for a role of mast cells in the evolution to congestive heart failure.

Mast cells are believed to be involved in the pathophysiology of heart failure, but their precise role in the process is unknown. This study examined the role of mast cells in the progression of heart failure, using mast cell-deficient (WBB6F1-W/W(v)) mice and their congenic controls (wild-type [WT] mice). Systolic pressure overload was produced by banding of the abdominal aorta, and cardiac function was monitored over 15 wk. At 4 wk after aortic constriction, cardiac hypertrophy with preserved left ventricular performance (compensated hypertrophy) was observed in both W/W(v) and WT mice. Thereafter, left ventricular performance gradually decreased in WT mice, and pulmonary congestion became apparent at 15 wk (decompensated hypertrophy). In contrast, decompensation of cardiac function did not occur in W/W(v) mice; left ventricular performance was preserved throughout, and pulmonary congestion was not observed. Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/W(v) mice. Treatment with tranilast, a mast cell-stabilizing agent, also prevented the evolution from compensated hypertrophy to heart failure. These observations suggest that mast cells play a critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure.

Animals↗
PubMed2002

Augmented expression of neuronal nitric oxide synthase in the atria parasympathetically decreases heart rate during acute myocardial infarction in rats.

BACKGROUND: Nitric oxide (NO) synthesized within sinoatrial cells recently has been shown to participate in the autonomic control of heart rate. We hypothesized that NO in the neuronal cells in the heart was increased and parasympathetically regulated heart rate after myocardial infarction (MI). METHODS AND RESULTS: We examined heart rate dynamics and neuronal NO synthase (nNOS) expression and activities in the atria of rats with MI 1, 3, 7, and 14 days after MI (n=7 to 22 for each group). Both the mRNA levels of nNOS in the atria determined by competitive reverse transcriptase-polymerase chain reaction and the protein levels determined by Western blotting were significantly increased compared with controls 1, 3, and 7 days after MI. nNOS activity in the atria 1 day after infarction was also increased in MI rats. nNOS immunoreactivity was observed in nerve fibers in the atria. After infusion of a specific inhibitor of nNOS and iNOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM) (50 mg/kg IV), heart rate was significantly (P<0.01) increased in MI rats compared with controls 1, 3, and 7 days after MI. The iNOS-specific inhibitor, 1400W (10 mg/kg SC), did not significantly affect the heart rate in rats with MI. The effect of TRIM was abolished by pretreatment with L-arginine (25 mg/kg IV) or by parasympathetic blockade with atropine but not by propranolol. There was a strong correlation (r=0.837, P<0.0001) between the nNOS protein expression and heart rate change after TRIM infusion. CONCLUSIONS: These results indicate that increased nNOS parasympathetically decreased heart rate via the production of NO in rats with acute MI.

Animals↗
PubMed2002

Basic fibroblast growth factor protects cardiac myocytes from iNOS-mediated apoptosis.

Basic fibroblast growth factor (bFGF) is an important angiogenic factor produced by hearts subjected to ischemia. However, the direct effects of bFGF on myocardial cells are unknown. Primary cultured cardiac myocytes from neonatal rats were stimulated with lipopolysaccharide (LPS), a potent inducer of inducible nitric oxide synthase (iNOS), in the presence or the absence of bFGF. LPS induced the expression of iNOS in cardiac myocytes, demonstrated at both mRNA and protein levels. We showed that LPS activated the apoptotic pathway, evidenced by TUNEL staining, DNA ladder formation, and morphologic features. LPS-induced apoptosis was blocked by the administration of L-NAME, an inhibitor of NOS. This indicates that LPS induces apoptosis via an iNOS-dependent pathway. Administration of bFGF completely inhibited myocardial cell apoptosis induced by hydrogen peroxide or acidic medium as well as LPS. To determine signaling pathways for this inhibitory effect, we utilized PD098059, an MEK-1-specific inhibitor. PD098059 blocked bFGF-induced activation of ERK (extracellularly responsive kinase)-1/2 and neutralized the apoptotic inhibitory effect of bFGF. These findings demonstrate that LPS induces myocardial cell apoptosis in an iNOS-dependent manner. The results also suggest that bFGF is a protective factor against myocardial cell apoptosis and that this protection requires the MEK-1-ERK pathway.

Animals↗
PubMed2002

Economic evaluation of the randomized aldactone evaluation study (RALES): treatment of patients with severe heart failure.

PURPOSE: To use data from the Randomized Aldactone Evaluation Study (RALES) to compare clinical outcomes and costs as part of the assessment of the economic implications of spironolactone treatment of advanced heart failure. METHODS: RALES was a randomized, double-blinded, placebo-controlled trial that enrolled participants who had severe heart failure and a left ventricular ejection fraction of no more than 35% and who were receiving standard therapy, including an angiotensin-converting enzyme inhibitor, a loop diuretic, and, in some cases, digoxin. We used a decision analytic model that incorporated data from participants in RALES as well as cost data from five countries that participated in the study. Costs were calculated for nonfatal hospitalizations, ambulatory care, spironolactone therapy, and death. The primary health outcome was quality-adjusted life-years saved (QALYS). Outcomes were evaluated for the first 35 months of observation in RALES. RESULTS: Spironolactone therapy during the first 35 months of follow-up in RALES increased quality-adjusted survival time (0.13 QALYS, 95% CI, 0.07 to 0.18) without increasing costs ($713 savings, 95% CI, $2,123 savings to $783 in costs). Spironolactone therapy either dominated placebo or had a ratio of cost per QALYS that was unlikely to exceed $20,300. These results were robust in both one-way and multiway sensitivity analyses. CONCLUSIONS: Even after implementation of current clinical guidelines, addition of spironolactone therapy provides an opportunity to further reduce the large clinical and economic burden of patients with heart failure.

Ambulatory Care↗
PubMed2002

Inotropic agents and immune modulation.

Since depression of myocardial contractility forms the basis for the development of heart failure, many attempts have been made to enhance the inotropic state of the failing heart by cardiotonic agent as the therapeutic modality. However, large scale clinical trials conducted in the Western societies revealed excess mortality in patients with heart failure received long-term treatment with inotropic agent. Therefore, all of these agents are now regarded as unsuitable for chronic heart failure treatment. In contrast, some inotropic agents with phosphodiesterase inhibitory properties exhibited potential benefits in Japanese patients. In Japan mortality due to heart disease is substantially lower than that found in all other Western countries. Thereby, chronic treatment with inotropic agent may be justified as the optimal care in the context of relief of symptoms and an improved quality of life. The salutary effects of these phosphodiesterase inhibitors appear to be related to anticytokine and immunomodulating effects as well as their cardiotonic action. These findings support the recent new concept that immune responses mediated by cytokines play an important role in the pathogenesis of heart failure.

Adjuvants, Immunologic↗
PubMed2002

Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats.

Cardiotrophin-1 (CT-1) stimulates longitudinal myocardial cell hypertrophy. We examined the expression of CT-1, leukemia inhibitory factor (LIF), and gp130 by competitive RT-PCR and Western blotting in Dahl salt-sensitive (DS) rats with a high-salt diet, which showed a distinct transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF). The expression levels of CT-1 mRNA and protein were significantly increased at the CHF stage compared with the LVH stage and age-matched Dahl salt-resistant (DR) rats (n = 6 for each group). mRNA expression of LIF was not changed in the left ventricle at any stage by RT-PCR. gp130 mRNA and protein levels of DS rats at 11 and 17 wk were significantly increased compared with age-matched DR rats. The isolated myocyte length of DS rats at 17 wk was the longest among the four groups of rats. The LV end-diastolic dimension (LVDd) of DS rats, determined by echocardiography, was significantly increased at the CHF stage. There was a significant correlation between the CT-1 protein level and LVDd. CT-1 may play a role in ventricular remodeling during transition from LVH to CHF in the rat hypertensive model.

Animals↗
PubMed2002

Correlation between the severity of clinicopathological parameters and whole blood interferon-alpha production capacity in active phase IgA nephropathy patients.

BACKGROUND/AIMS: Patients with IgA nephropathy (IgA-N) are thought to have immune system disorders that frequently result in high serum IgA levels and a relatively high susceptibility to upper respiratory infections. AIMS: To clarify the influence of the specific immune response of IgA-N patients on the clinicopathological features of the disease, we measured the whole-blood-producing capacity of interferon-alpha (IFNalpha-PC). We then compared these findings with clinical and histopathological parameters, including tissue macrophage infiltration, during both histologically active and latent phases. PATIENTS AND METHODS: Fifty-one inpatients with IgA-N and 70 healthy controls were examined. According to the histological findings, 32 patients had disease in the active phase (AP), and 19 were in the latent phase (LP). RESULTS: In AP patients, IFNalpha-PC showed positive correlations to serum creatinine, blood urea nitrogen, serum beta2-microglobulin (s-beta2MG), urinary total protein (U-TP), and urinary beta2MG, in addition to the number of infiltrated macrophages per area of interstitium. In LP patients, negative correlations were shown between IFNalpha-PC and s-beta2MG, U-TP, and U-N-acetyl-beta-D-glucosaminidase. CONCLUSION: A significant positive relationship exists between IFNalpha-PC and the clinicopathological parameters of deteriorated renal lesions in the AP but not in the LP. Thus, the immune status influencing the functional damage may differ between these two phase.

Adult↗
PubMed2002

Heminephrectomy causes the progression of glomerulosclerosis and apoptosis in high IgA strain ddY mice.

BACKGROUND: The reduction in nephrons in IgA nephropathy is critical to the prognosis of this disease. However, the immunopathological mechanism of the modifications seen in glomerular lesions is not clear. We thus investigated the influence of nephron reduction by heminephrectomy on renal lesions in a high immunoglobulin A inbred strain of ddY mouse (HIGA mouse), which shows progressive mesangial sclerosis with elevated renal expression of transforming growth factor (TGF)-beta. METHODS: Five-week-old HIGA mice were heminephrectomized (Nx), and were evaluated in comparison with a sham-operated group (S) at 40 weeks old. Histological findings, immunoglobulin depositions (IgG, IgA, and IgM), and expressions of cytokine and extracellular matrix proteins (TGF-beta, fibronectin, collagen type I and IV) were analysed. PCNA and TUNEL stainings were performed with electron microscopic detection of apoptosis. Tissue renin-angiotensin systems (RAS) were also investigated by real-time quantitative RT-PCR. RESULTS: In the Nx group, the glomerular tuft area and ratio of mesangial matrix area per tuft were significantly increased, and the glomerular cell count per tuft area was significantly decreased. Glomerular immunoglobulin deposits of IgG, IgA, and IgM in Nx were all significantly expanded in the paramesangium. The glomerular expressions of TGF-beta and the extracellular matrix proteins were significantly increased in Nx mice. In contrast to the significant decrease of PCNA-positive cells, TUNEL-positive cells were significantly increased in Nx. Angiotensin-converting enzyme (ACE) was significantly increased in the renal cortex of Nx. CONCLUSION: Simple heminephrectomy, other than 5/6 renal ablation, of HIGA mice may be a potential model for research into the progressive glomerulosclerosis of human IgA nephropathy. The pathological role of apoptosis is apparently involved in these disease processes, possibly through upregulated RAS.

Animals↗
PubMed2002

Circulating hepatocyte growth factor as a diagnostic marker of thrombus formation in patients with cerebral infarction.

Circulating levels of hepatocyte growth factor (HGF) are increased in the early stage of an acute myocardial infarction because of arterial thrombosis. The purpose of this study was to use a new sensitive enzyme-linked immunosorbent assay to investigate whether circulating HGF is increased in patients with cerebral infarction. Circulating HGF was measured in 32 patients with cerebral infarction on admission to hospital and on days 2, 3, 7 and 14 after the onset of symptoms. Serum HGF levels exceeded the mean value +2SD (329pg/ml) measured in controls in 10 of 20 patients (50%) within 6 h after onset and in 15 of 32 patients (47%) within 24 h. Plasma D-dimer was increased in more than half of the patients with elevated HGF values. HGF levels in 16 patients who were measured serially were persistently increased throughout the study period. The results suggests that circulating HGF is a reliable early marker of cerebral infarction, and that this new sensitive HGF assay may be useful for diagnosing cerebral thrombosis.

Aged↗
PubMed2002

Epidemiologic and clinical characteristics of cardiomyopathies in Japan: results from nationwide surveys.

Nationwide clinico-epidemiological surveys of cardiomyopathies in Japan were carried out. Disorders surveyed included idiopathic dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular dysplasia (ARVD), mitochondrial disease, Fabry's disease of the heart and prolonged Q-T interval syndrome. The total number of patients was estimated at 17,700 for DCM, 21,900 for HCM, 300 for RCM, 520 for ARVD, 640 for mitochondrial disease, 150 for Fabry's disease of the heart, and 1,000 for prolonged Q-T interval syndrome. The prevalence of both DCM and HCM was higher in men than women: the male-to-female ratios were 2.6 and 2.3 for DCM and HCM, respectively. Detailed data on patients with DCM or HCM were collected by a follow-up survey. In 1 year more patients with DCM (5.6%) died than with HCM (2.8%): congestive heart failure (CHF) and arrhythmias were the leading causes of death for DCM and HCM, respectively. Angiotensin converting enzyme inhibitors (64.6%) and beta-adrenergic blockers (40.9%) are commonly used to treat the CHF complicating DCM and may be associated with the clinical improvement in a significant number of DCM patients. Thus, the nationwide surveys of Japanese patients have yielded important current epidemiological and clinical information on the characteristics of cardiomyopathies in Japan.

Adolescent↗
PubMed2002

Shunt between the ventricular chamber and coronary arteries preserves left ventricular function in acute myocardial infarction.

It is controversial whether newly created channels made by transmyocardial laser revascularization are functionally significant, so the present study evaluated the shunt flow from the left ventricular (LV) cavity to the ischemic myocardium in 51 patients with acute myocardial infarction (AMI) caused by complete occlusion of the proximal left anterior descending coronary artery. All patients underwent left heart catheterization within 24 h of onset and all underwent successful coronary reperfusion using primary coronary angioplasty with no angiographic restenosis on follow-up coronary angiography (CAG). The presence of the LV shunt flow was evaluated by selective left CAG after successful reperfusion. The LV global ejection fraction (EF) and regional function (centerline method) were analyzed by ventriculography in both the acute and chronic phases. The patients were divided into the 3 groups (Group A, no LV shunt without collaterals, n=20; Group B, no LV shunt with collaterals, n=24; Group C, LV shunt with collaterals, n=7). There was no difference in the grade of collateral circulation between Groups B and C. The improvements in LVEF and regional function from the acute phase to the chronic phase were significantly greater in Group C than in Groups A and B. Not only collateral circulation but also LV shunt contributes to the functional recovery of infarct myocardium in patients with AMI.

Adult↗
PubMed2002

Role of KCNQ1 in the cell swelling-induced enhancement of the slowly activating delayed rectifier K(+) current.

Cell swelling enhances a slowly activating delayed rectifier K(+) current (I(Ks)) in cardiac cells. This investigation was undertaken to determine which of the two structural units reconstituting the I(Ks) channel, KCNQ1 (KvLQT1) and KCNE1 (minK/IsK), plays a key role in the cell swelling-induced I(Ks) enhancement and to dissect a possible involvement of tyrosine phosphorylation therein. KCNQ1 was transiently expressed alone or together with KCNE1 in a heterologous mammalian cell line. Two distinct whole-cell membrane currents were separately observed during the exposure of transfected cells to various degrees of hyposmotic solutions. A hyposmotic challenge (0.7 times control osmolarity) resulted in about a twofold increase not only in the heteromeric KCNQ1/KCNE1, but also in the homomeric KCNQ1 channel currents. There was no significant difference in the incremental ratio of current amplitude in response to hyposmotic stress between the two KCNQ1-related currents, and the cells expressing the heteromeric channels swelled less than those with the homomeric channels or without the exogenous ones. The cell swelling-induced I(Ks) enhancement was not affected by a protein tyrosine kinase (PTK) inhibitor, by genistein (50 microM), or by an inhibitor of phosphotyrosine phosphatase (PTP), orthovanadate (500 microM), or a nonhydrolyzable ATP analogue, AMP-PNP (5 mM). Taken together, it is very likely that KCNQ1 might primarily participate in the I(Ks) enhancement by osmotic cell swelling. The obligatory dependence of the I(Ks) augmentation on PTK activity remained to be demonstrated, at least, in this expression system.

Animals↗