Biomedical subjects

Y Ono

Publications and source records attributed to Y Ono.

At least 55 records · Page 3Linked to original sources

PubMed2002

[Modified bentall operation using composite graft without resection of aortic valve].

A 27-year-old male whose diagnoses were aortic dissection (Stanford A), aortic regurgitation, annulo-aortic ectasia, and Marfan syndrome underwent modified Bentall operation using composite graft and total arch replacement. Modification of proximal suture without resection of aortic valve like intravalvular implantation might have resulted in good recovery without blood transfusion. Another 63-year-old male who suffered from spontaneous aortic rupture with aortic regurgitation also underwent modified Bentall operation in the similar manner as the first case with good result. Spontaneous aortic rupture reported here is a rare case, and operation is thought to be prerequisite for the patient who suffers from this disease to survive.

Adult↗

PubMed2001

Enantioselective intramolecular aromatic [4 + 4] photocycloaddition in crystalline state: parameters for reactivity.

Photoreactivity of seven 9-anthryl-N-(naphthylcarbonyl)carboxamide derivatives, 1a-g, in their intramolecular [4 + 4] photocycloadditions in solid state is discussed on the basis of their single-crystal X-ray analyses. The distances (d(1) and d(2)) between the two carbon atoms to be reacted, the angles (theta(1) and theta(2)), and the torsion angle (theta(3)) between the anthracene and naphthalene rings were chosen as structural parameters for reactivity. For 1a and 1e, the first example of absolute asymmetric synthesis in [4 + 4] photocycloaddition was attained. [reaction: see text]

Journal Article↗

PubMed2001

Apoptosis and glomerular injury after prolonged nitric oxide synthase inhibition in spontaneously hypertensive rats.

This study was designed to investigate the relationship between apoptosis and glomerular injury in spontaneously hypertensive rats (SHR) with hypertensive disease that was exacerbated by inhibition of NO synthesis. Development of glomerular cell apoptosis was evaluated by assessment of renal hemodynamics, glomerular morphometric changes, and participation of the renin-angiotensin system. Three groups of 20-week-old SHR were investigated: control male SHR and 2 similar groups given 2 doses of N(G)-nitro-L-arginine methyl ester (L-NAME, 50 or 80 mg/L, respectively) for 3 weeks. Mean arterial pressure and renal vascular resistance increased, whereas effective renal plasma flow and glomerular filtration rate were diminished by L-NAME. The small artery wall/lumen ratio increased as the glomerular-tuft area diminished. Renal cortical tissue levels of angiotensin II increased in response to the L-NAME, thereby inducing afferent arteriolar injury. Apoptosis and proliferative index (PCNA) of nonsclerotic glomeruli were induced by the low-dose L-NAME as the glomerular cell number decreased. In contrast, the PCNA index was downregulated with the high-dose L-NAME. These results indicate that angiotensin II activation, induced by L-NAME, was related to glomerular cell deletion and apoptosis together with the pathophysiological changes of severe nephrosclerosis and impaired renal dynamics.

Angiotensin II↗

PubMed2001

Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer.

BACKGROUND: Dexamethasone, a synthetic glucocorticoid, has clinical benefit in patients with hormone-refractory prostate cancer (HRPC), but the mechanisms responsible for its effects are unknown. The nuclear factor-kappaB (NF-kappaB)-dependent cytokine interleukin (IL) 6 (IL-6) is thought to stimulate growth of HRPC. Because dexamethasone interferes with NF-kappaB activation, we determined whether dexamethasone inhibits prostate cancer growth by working through the glucocorticoid receptor (GR) to interfere with NF-kappaB-IL-6 pathway. METHODS: Three human prostate cancer cell lines (DU145, PC-3, and LNCaP) were assessed for GR expression and responsiveness to dexamethasone. Levels of GR, NF-kappaB, and the cytoplasmic NF-kappB inhibitor IkappaBalpha were determined by western blotting and of IL-6 by enzyme immunoassay. The subcellular localization of NF-kappaB was analyzed by immunofluorescence. The effects of dexamethasone (thrice weekly injections of 1 microg/mouse) on DU145 xenografts in nude and severe combined immunodeficient (SCID) mice were evaluated. GR expression in human prostate cancers was assessed by immunohistochemistry. All statistical tests were two-sided. RESULTS: Dexamethasone dose dependently decreased GR levels and inhibited the growth of DU145 and PC-3 but not LNCaP cells (DU145 cells, P< .001; PC-3 cells, P = .009). Dexamethasone increased IkappaBalpha protein levels and the cytosolic accumulation of NF-kappaB in DU145 cells and decreased secreted IL-6 levels to 37 pg/mL (95% confidence interval [CI] = 33 pg/mL to 41 pg/mL), compared with 164 pg/mL (95% CI = 162 pg/mL to 166 pg/mL) secreted by ethanol-treated control cells. Dexamethasone inhibited the growth of DU145 xenografts in nude (P = .006) and SCID (P = .026) mice without affecting GR levels. Eight of 16 human prostate cancers expressed GR at high levels (>or=30% GR-positive cells). CONCLUSION: Dexamethasone inhibited the growth of GR-positive cancers, possibly through the disruption of the NF-kappaB-IL-6 pathway.

Androgens↗

PubMed2001

Specific interaction of the potassium channel beta-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system.

Ion-channel beta-subunits are ancillary proteins that co-assemble with alpha-subunits to modulate gating kinetics and enhance stability of multimeric channel complexes. They provide binding sites for other regulatory proteins and are medically important as the targets of many pharmacological compounds. MinK is the beta-subunit of the slow activating component of the delayed rectifier potassium current (I(Ks)) channel, and associates with the alpha-subunit, KvLQT1. We report here that minK specifically interacts with the sarcomeric Z-line component, T-cap (also called telethonin). In vitro interaction studies indicated that the cytoplasmic domain of minK specifically binds to the sixteen C-terminal residues of T-cap; these residues are sufficient for its interaction with minK. Consistent with our in vitro studies, immunofluorescence staining followed by confocal analysis revealed that both minK and T-cap are localized within the Z-line region in cardiac muscle. Striated staining of minK was observed in non-washed, membrane-intact cardiac myofibrils, but not in well-washed, membrane-removed cardiac myofibrils, suggesting that minK localizes on T-tubular membranes surrounding the Z-line in the inner ventricular myocardium. Together with our previous data on the colocalization and interaction of T-cap with the N-terminus of the giant protein titin in the periphery of the Z-line, these data suggest that T-cap functions as an adapter protein to link together myofibrillar components with the membranous beta-subunit of the I(Ks) channel. We speculate that this interaction may contribute to a stretch-dependent regulation of potassium flux in cardiac muscle, providing a "mechano-electrical feedback" system.

Amino Acid Sequence↗

PubMed2001

Use of marginal organs from non-heart-beating cadaveric kidney donors.

BACKGROUND: The severe shortage of cadaver donor kidneys for transplantation has prompted many centers to utilize older donor kidneys, which have been associated with lower graft survival rates. The aim of the present study was to examine the availability and feasibility of considering kidneys from donors over the age of 60. METHOD: We studied 252 cadaveric renal transplant recipients (156 males, 96 females) who received kidneys from uncontrolled non-heart-beating donors between 1987 and 1997. We performed in situ cooling with especially designed double-balloon catheters to minimize warm ischemic kidney damage. Recipients were classified according to donor age ( age 60), and we examined graft survival rates. All patients were followed for a minimum of 1 year after transplantation. RESULTS: Graft survival rates for recipients of kidneys from the older donor group at 1, 5, and 10 years after transplantation were 77%, 37%, and 30%, respectively. Corresponding values for the younger donor kidney recipients were 87%, 64%, and 47%, respectively (P=0.0011). Improved survival rates were noted when older kidneys were used for lighter weight recipients (<54 kg). No other significant factors impacted on older donor graft survival rates. CONCLUSION: Older donor kidneys are associated with poorer graft survival rates. However, kidney transplants from older donors can be quite effective in lighter weight recipients (<54 kg).

Adult↗

PubMed2001

Severely impaired cardiac autonomic nervous activity after the Fontan operation.

BACKGROUND: Elevated neurohumoral activity and an abnormal cardiopulmonary response to exercise are well-established characteristics in patients after the Fontan operation. However, there have been few studies addressing cardiac autonomic nervous activity (CANA) in these patients. METHODS AND RESULTS: We evaluated CANA in 63 post-Fontan patients and 44 controls. Cardiac parasympathetic nervous activity (PSNA) was estimated by heart rate (HR) changes after cholinergic blockade, HR variability, and arterial baroreflex sensitivity. Cardiac sympathetic nervous activity was estimated by the heart to mediastinum [(123)I]metaiodobenzylguanidine activity ratio (H/M) and the HR increase (DeltaHR) after isoproterenol infusion (beta). DeltaHR and peak oxygen uptake (VO(2)) were measured by exercise test. There was no difference in beta between the Fontan group and controls. PSNA and H/M were markedly lower than in controls (P<0.001). PSNA and beta were related to DeltaHR (P<0.05); however, peak VO(2) was not correlated with DeltaHR. Neither PSNA nor H/M was associated with clinical features, including hemodynamics, type of repair, number of surgical procedures, age at Fontan operation, or follow-up period, and administration of an angiotensin-converting enzyme inhibitor did not improve the impaired CANA in these patients. CONCLUSIONS: After the Fontan procedure, postsynaptic beta-sensitivity is maintained and is important in DeltaHR during exercise as is PSNA, although DeltaHR does not determine exercise capacity. The lack of a relationship between CANA and clinical features implies that, in addition to surgical damage, the Fontan circulation per se may impair CANA. Angiotensin-converting enzyme inhibitor administration does not change this abnormality.

Adolescent↗

PubMed2001

Sporadic testicular germ cell cancers do not exhibit specific alteration in CAG/CTG repeats containing genes expressed in human testis.

CAG/CTG repeat expansions in genomic DNA of testicular tumour cell lines, and germline DNA from members of families predisposed to this malignancy, have been previously described. In order to identify genes possibly concerned by this alteration, we attempted to clone all possible human testis cDNA containing at least five CAG/CTG repeats. Thirty-four different transcripts were identified. By using PCR and non denaturing gel electrophoresis, we determined the size of their repeats, as well as their polymorphisms in a collection of human testicular germ cell tumours and the normal surrounding tissues. For all tested genes, we detected the presence of several species of the same mRNA for each person. Nine genes exhibited specific patterns of expression among different groups of individuals, indicative of polymorphism. None of these polymorphisms was related to human testicular tumours.

Anticipation, Genetic↗

PubMed2001

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Adolescent↗

PubMed2001

Histamine-induced vasoconstriction involves phosphorylation of a specific inhibitor protein for myosin phosphatase by protein kinase C alpha and delta isoforms.

Histamine stimulus triggers inhibition of myosin phosphatase-enhanced phosphorylation of myosin and contraction of vascular smooth muscle. In response to histamine stimulation of intact femoral artery, a smooth muscle-specific protein called CPI-17 (for protein kinase C-potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kDa) is phosphorylated and converted to a potent inhibitor for myosin phosphatase. Phosphorylation of CPI-17 is diminished by pretreatment with either or GF109203x, suggesting involvement of multiple kinases (Kitazawa, T., Eto, M., Woodsome, T. P., and Brautigan, D. L. (2000) J. Biol. Chem. 275, 9897--9900). Here we purified and identified CPI-17 kinases endogenous to pig artery that phosphorylate CPI-17. DEAE-Toyopearl column chromatography of aorta extracts separated two CPI-17 kinases. One kinase was protein kinase C (PKC) alpha, and the second kinase was purified to homogeneity as a 45-kDa protein, and identified by sequencing as PKC delta. Purified PKC delta was 3-fold more reactive with CPI-17 compared with myelin basic protein, whereas purified PKC alpha and recombinant RhoA-activated kinases (Rho-associated coiled-coil forming protein Ser/Thr kinase and protein kinase N) showed equal activity with CPI-17 and myelin basic protein. inhibited CPI-17 phosphorylation by purified PKC delta with IC(50) of 0.6 microm (in the presence of 0.1 mm ATP) or 14 microm (2.0 mm ATP). significantly suppressed CPI-17 phosphorylation in smooth muscle cells, and the contraction of permeabilized rabbit femoral artery induced by stimulation with phorbol ester. GF109203x inhibited phorbol ester-induced contraction of rabbit femoral artery by 80%, whereas a PKC alpha/beta inhibitor, Go6976, reduced contraction by 47%. The results imply that histamine stimulation elicits contraction of vascular smooth muscle through activation of PKC alpha and especially PKC delta to phosphorylate CPI-17.

Amides↗

PubMed2001

Influence of ventricular morphology on aerobic exercise capacity in patients after the Fontan operation.

OBJECTIVES: This study investigated the influences of ventricular morphology, hemodynamics and clinical findings on exercise capacity in patients after the Fontan operation. BACKGROUND: Determinants of exercise capacity after the Fontan operation remain unclear. METHODS: Peak oxygen uptake (PVo2) was determined in 105 patients by exercise test and compared to hemodynamics and clinical findings. Patients were divided into three groups based on ventricular morphology: those with a right ventricle (group RV), a biventricle (group BV) and a left ventricle (group LV). RESULTS: Ten patients with atrioventricular valve regurgitation (AVVR) or hypoxia exhibited a low PVo2. After excluding these patients, although PVo2 did not correlate with hemodynamics, except ventricular ejection fraction (p < 0.02), it correlated with age at the Fontan operation and exercise test (p < 0.002). The PVo2 was higher in group LV (63+/-9%) than in groups RV (55+/-9%) and BV (55+/-12%) (p < 0.01), while an inverse correlation between PVo2 and age at operation was demonstrated only in group RV (p < 0.05). Groups RV or BV and age at exercise test were associated with a lower PVo2, whereas group LV was an independent predictor of a higher PVo2 (p < 0.01). During 4.2 years of follow-up, a decrease in peak heart rate was related to a decrease in PVo2 (p < 0.05). The PVo2 decreased in group RV (p < 0.01). CONCLUSIONS: In addition to AVVR, hypoxia, and heart rate response, ventricular morphology is related to exercise capacity. Early Fontan operation may be beneficial in terms of exercise capacity, especially in the group RV patients.

Adolescent↗

PubMed2001

A new phosphoglycerolipid, 'phosphatidylglucose', found in human cord red cells by multi-reactive monoclonal anti-i cold agglutinin, mAb GL-1/GL-2.

Cord red cell membranes express many differentiation-related molecules. To study such molecules, we have established human cell lines, termed GL-1 and GL-2, by the Epstein-Barr virus transformation method, both of which produce monoclonal anti-i cold agglutinin [Y. Nagatsuka et al., Immunol. Lett. 46 (1995) 93-100]. Thin layer chromatography immunoblotting analysis revealed that these antibodies had broad specificities reacting with a variety of glycolipid antigens. Of the immunoreactive lipid antigens, a new phosphoglycerolipid containing glucose from human cord red cells was found. The isolated lipid was unstable to alkaline hydrolysis and contained glucose as a sole sugar. Secondary ion mass spectrum-collision-induced dissociation mass spectrometric analysis of this lipid gave the main molecular ion peak at m/z 885 corresponding to phosphatidylhexose. This antigen was susceptible to phospholipases A2, C and D but resistant to phosphatidylinositol-specific phospholipase C. Two-dimensional nuclear magnetic resonance spectroscopy confirmed that glucose is linked to the sn-glycerol 3-phosphate residue with a beta-anomeric configuration. Based upon these combined results, we identified this lipid as phosphatidyl-beta-D-glucose. This is the first report showing the presence of the glucosylated glycerophospholipid in mammalian sources.

Agglutinins↗

PubMed2001

Synthesis and antifungal activities of novel 1,3-beta-D-glucan synthase inhibitors. Part 2.

Highly potent 1,3-beta-D-glucan synthase inhibitors, 7b, 10a, 10b and 12, have been identified by the chemical modification of the ornithine residue of a fungicidal macrocyclic lipopeptidolactone, RO-09-3655 (1), isolated from the cultured broth of Deuteromycotinia spp. These compounds showed stronger antifungal activity against systemic candidiasis as well as pulmonary aspergillosis in mice, and less hepatotoxicity as compared with 1.

Animals↗

PubMed2001

PKN regulates phospholipase D1 through direct interaction.

The association of phospholipase (PLD)-1 with protein kinase C-related protein kinases, PKNalpha and PKNbeta, was analyzed. PLD1 interacted with PKNalpha and PKNbeta in COS-7 cells transiently transfected with PLD1 and PKNalpha or PKNbeta expression constructs. The interactions between endogenous PLD1 and PKNalpha or PKNbeta were confirmed by co-immunoprecipitation from mammalian cells. In vitro binding studies using the deletion mutants of PLD1 indicated that PKNalpha directly bound to residues 228-598 of PLD1 and that PKNbeta interacted with residues 1-228 and 228-598 of PLD1. PKNalpha stimulated the activity of PLD1 in the presence of phosphatidylinositol 4,5-bisphosphate in vitro, whereas PKNbeta had a modest effect on the stimulation of PLD1 activity. The stimulation of PLD1 activity by PKNalpha was slightly enhanced by the addition of arachidonic acid. These results suggest that the PKN family functions as a novel intracellular player of PLD1 signaling pathway.

Animals↗

PubMed2001

Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes.

Cardiomyocytes are terminally differentiated cells characterized as withdrawal cell-cycle machinery, but nonetheless they are known to express cell-cycle regulators. Because many proteins related to the cell cycle induce apoptosis in proliferating cells, we examined the involvement of these proteins in the apoptosis pathway in cardiomyocytes. Primary rat cardiomyocytes were exposed to a severe hypoxic condition to induce apoptosis. The apoptosis rate of cardiomyocytes increased to approximately 40% under 24 hours of hypoxia as evaluated by the TUNEL method. The cyclin A protein level assessed by immunoblot analysis accumulated in a time-dependent manner in cardiomyocytes, but there was no increase in nonmyocytes. Hypoxia increased the activity of cyclin A-associated kinase but not the activity of cyclin E-associated kinase, and the apoptosis was inhibited by infection of dominant-negative cdk2 adenovirus, suggesting that cyclin A and its associated kinase play significant roles in the apoptosis of cardiomyocytes. To investigate the cyclin A-mediated apoptosis, we infected cultured cells with cyclin A adenovirus. Apoptosis was induced in 63+/-12% of the infected cardiomyocytes in contrast to only 12+/-3% of the LacZ-infected control cells. In addition, the cells in the hypoxic condition showed an increase in caspase-3 activity and a subsequent decrease in p21(cip1/waf1) protein, which is partly cleaved by caspase-3. These findings confirm that cyclin A-associated kinase mediates hypoxia-induced apoptosis in cardiomyocytes, and they also suggest that additional elements of the cell-cycle-dependent machinery participate in this mechanism.

Animals↗

PubMed2001

Enantioselective metabolism of propanolol in isolated hepatocytes prepared from untreated, PB- or 3-MC-pretreated rats.

The present paper describes the metabolism of a chiral drug propranolol (PL) using isolated hepatocytes freshly prepared from untreated, PB- or 3-MC-pretreated rats. In order to examine not only the existence of enantioselectivity but also the effect of enzyme inducer (PB or 3-MC) on PL metabolism, 500 microM PL (RS-PL, R(+)-PL or S(-)-PL) was incubated at 37 degrees C using 8 x 10(6) cells/ml isolated rat hepatocytes. Then, the elimination amount of PL and the formation amounts of eight kinds of the metabolites including ring hydroxylated metabolites (4-OH-, 5-OH- and 7-OH-PL) and side chain metabolites (NDP, AcNDP, PGL, NLA and NAA) were simultaneously determined by HPLC. By 3-MC- and PB-pretreatment, a significant increase was noticed in PL elimination and also in the formation of PL metabolites, NDP, NLA and NAA. Furthermore, the presence of enantioselectivity was observed, i.e. the substrate R(+)-PL was always eliminated faster than the substrate S(-)-PL. Regarding the metabolite formation, NDP, AcNDP and NAA were dominantly produced from R(+)-PL, and NLA, PGL and the ring hydroxylated metabolites from S(-)-PL. In all cases of PL elimination and the metabolite formation, the amounts of the metabolites derived from RS-PL indicated the mean values of the respective amounts derived from R(+)-PL and S (-)-PL. Using the three kinds of isolated rat hepatocytes mentioned above, the kinetic parameters of NDP-formation at 37 degrees C for 10 min were calculated using RS-PL, R(+)-PL or S(-)-PL as a substrate. From the pseudo values of V'max/K'm (microliter/min.8 x 10(6) cells), the easiest formation of NDP from R(+)-PL was observed in the rat hepatocyte system pretreated with 3-MC.

Animals↗

PubMed2001

Evaluation of oxidative stress during apoptosis and necrosis caused by carbon tetrachloride in rat liver.

After 12, 18, and 24 h of oral administration of carbon tetrachloride (as a 1:1 mixture with mineral oil: 4 ml/kg body weight) to rats, the activity of caspase-3-like protease in the liver increased significantly compared to that in the control group that was given mineral oil (4 ml/kg). In plasma, the activity of caspase-3 was barely detectable in the control rat, but increased significantly 24 h after drug administration along with a dramatic increase in glutamate oxaloacetate transaminase. These results indicate that carbon tetrachloride causes apoptosis in the liver by activating caspase-3, which is released to plasma by secondary necrosis. After 18 and 24 h of carbon tetrachloride administration, the liver concentration of hydrophilic vitamin C was decreased significantly, while that of hydrophobic vitamin E was not affected. The plasma concentration of vitamins C and E was not influenced significantly. These results suggest that carbon tetrachloride induces oxidative stress mainly in the aqueous phase of the liver cell.

Animals↗

PubMed2001

Complex gangliosides as cell surface inhibitors for the ecto-NAD+ glycohydrolase of CD38.

Leukocyte cell surface antigen CD38 is a single-transmembrane protein whose extracellular domain has catalytic activity for NAD(+) glycohydrolase (NADase). We previously reported that b-series gangliosides inhibit the NADase activity of the extracellular domain of CD38 expressed as a fusion protein [Hara-Yokoyama, M., Kukimoto, I., Nishina, H., Kontani, K., Hirabayashi, Y., Irie, F., Sugiya, H., Furuyama, S., and Katada, T. (1996) J. Biol. Chem. 271, 12951-12955]. In the present study, we examined the effect of exogenous gangliosides on the NADase activity of CD38 on the surface of retinoic acid-treated human leukemic HL60 cells and CD38-transfected THP-1 cells. After incubation of the cells with G(T1b), inhibition of NADase activity was observed. The time course of inhibition was slower than that of the incorporation of G(T1b) into the cells, suggesting that incorporation into the cell membranes is a prerequisite for inhibition. Inhibition occurred efficiently when G(T1b) and CD38 were present on the same cells (cis interaction) rather than on different cells (trans interaction). Although gangliosides may affect localization of cell surface proteins, indirect immunofluorescence intensity due to CD38 was not affected after G(T1b) treatment. Comparison of the effect of G(T1b) and G(D1a) indicates that the tandem sialic acid residues linked to the internal galactose residue of the gangliotetraose core are crucial to the inhibition. These results suggest a novel role of complex gangliosides for the first time as cell surface inhibitors of CD38 through specific and cis interaction between the oligosaccharide moiety and the extracellular domain.

ADP-ribosyl Cyclase↗