Biomedical subjects

M Bhatia

Publications and source records attributed to M Bhatia.

At least 73 records · Page 4Linked to original sources

PubMed2000

Characterization of chemokine receptors expressed in primitive blood cells during human hematopoietic ontogeny.

Chemokines are capable of regulating a variety of fundamental processes of hematopoietic cells that include proliferation, differentiation, and migration. To evaluate potential chemokine signaling pathways important to the regulation of primitive human hematopoietic cells, we examined chemokine receptor expression of highly purified subpopulations of uncommitted human blood cells. CXCR1-, CXCR2-, CXCR4-, and CCR5-expressing cells were detected by flow cytometry among human blood subsets depleted of lineage-restricted cells (Lin(-)) derived from adult bone marrow, mobilized peripheral blood, cord blood (CB), and circulating fetal blood. Although these chemokine receptors could be detected on Lin(-) cells throughout human development, only CXCR4 could be detected in CD34(-)CD38(-)Lin(-) and CD34(+)CD38(-)Lin(-) subfractions enriched for stem cell function, suggesting that independent of ontogeny, CXCR4-mediated signals are critical to primitive hematopoiesis. Distinct to other stages of human hematopoietic development, primitive CB cells expressed higher levels of CXCR1, CXCR2, CCR5, and CXCR4 on both CD34(-)CD38(-)Lin(-) and CD34(+)CD38(-)Lin(-) subsets. Isolation of these fractions revealed expression of additional chemokine receptors CCR7, CCR8, and Bonzo (STRL133), whereas BOB (GPR15) could not be detected. Our study illustrates that rare uncommitted hematopoietic cells express chemokine receptors not previously associated with primitive human blood cells. Based on these results, we suggest that signaling pathways mediated by chemokine receptors identified here may play a fundamental role in hematopoietic stem cell regulation and provide alternative receptor targets for retroviral pseudotyping for genetic modification of repopulating cells.

Adult↗

PubMed2000

Usefulness of short term video-EEG monitoring in children with frequent intractable episodes.

A prospective study was done to evaluate the role of short-term Video EEG (VEEG) recording in assessing the nature of clinical behaviour and in classification of seizures in children with frequent intractable seizure episodes. Forty five children upto 12 years of age with frequent intractable seizure episodes (> or =3/week) were included in the study. VEEG was done on an outpatient basis until an event was recorded or for a minimum period of 6 hours. The events were detected in 78% of cases. The seizures were classified in all children with recorded events and seizure classification was changed in 22%. Anti-epileptic drugs could be stopped or reduced in 11%. Short term VEEG monitoring was useful in characterising events and in classification of seizures in children with frequent, intractable seizure episodes. Use of this investigation as a screening procedure for diagnosis in children with frequent episodes is stressed, thereby reducing the cost associated with prolonged VEEG recordings and disability associated with misdiagnosis of epilepsy.

Child↗

PubMed1999

Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells.

The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34(+)CD38(-)Lin- stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor beta, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34(+)CD38(-) phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34(+) CD38(-)Lin- cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.

Activin Receptors↗

PubMed1999

The role of intercellular adhesion molecule 1 and neutrophils in acute pancreatitis and pancreatitis-associated lung injury.

BACKGROUND & AIMS: Intercellular adhesion molecule 1 (ICAM-1) and neutrophils play important roles in many inflammatory processes, but their importance in both acute pancreatitis and pancreatitis-associated lung injury has not been defined. METHODS: To address this issue, mice that do not express ICAM-1 were used and depleted of neutrophils by administration of antineutrophil serum. Pancreatitis was induced by administering either supramaximal doses of the secretagogue cerulein or feeding a choline-deficient, ethionine-supplemented diet. The severity of pancreatitis was evaluated by quantitating serum amylase, pancreatic edema, acinar cell necrosis, and pancreas myeloperoxidase activity (i.e., neutrophil content). Lung injury was evaluated by quantitating lung myeloperoxidase activity and pulmonary microvascular permeability. ICAM-1 was quantitated by enzyme-linked immunosorbent assay and was localized by light-microscopic immunohistochemistry. RESULTS: It was found that serum, pancreas, and lung ICAM-1 levels increase during pancreatitis. Both pancreatitis and the associated lung injury are blunted, but not completely prevented, in mice deficient in ICAM-1. Neutrophil depletion also reduces the severity of both pancreatitis and lung injury. However, the combination of neutrophil depletion with ICAM-1 deficiency does not reduce the severity of pancreatitis or lung injury to a greater extent than either neutrophil depletion or ICAM-1 deficiency alone. Neither pancreatitis nor pancreatitis-associated lung injury are completely prevented by ICAM-1 deficiency, neutrophil depletion, or combined ICAM-1 deficiency plus neutrophil depletion. CONCLUSIONS: The observations indicate that ICAM-1 plays an important, neutrophil-mediated, proinflammatory role in pancreatitis and pancreatitis-associated lung injury. The studies also indicate that ICAM-1 and neutrophil-independent events also contribute to the evolution of pancreatitis and lung injury in these models.

Acute Disease↗

PubMed1999

Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice.

Little is known about the cell types or mechanisms that underlie the engraftment process. Here, we have examined parameters affecting the engraftment of purified human Lin-CD34+CD38- normal and AML cells transplanted at limiting doses into NOD/SCID recipients. Mice transplanted with 500 to 1000 Lin-CD34+CD38- cord blood (CB) or AML cells required the co-transplantation of accessory cells (ACs) or short-term in vivo cytokine treatment for engraftment, whereas transplantation of higher doses (>5000 Lin-CD34+CD38- cells) did not show these requirements suggesting that ACs are effective for both normal and leukemic stem cell engraftment in this model. Mature Lin+CD34- and primitive Lin-CD34+CD38+ cells were capable of acting as ACs even though no repopulating cells are present. Cytokine treatment of NOD/SCID mice could partially replace the requirement for co-transplantation of AC. Furthermore, no difference was seen between the percentage of engrafted mice treated with cytokines for only the first 10 days after transplant compared to those receiving cytokines for the entire time of repopulation. Surprisingly, no engraftment was detected in mice when cytokine treatment was delayed until 10 days posttransplant. Together, these studies suggest that the engraftment process requires pluripotent stem cells plus accessory cells or cytokine treatment which act early after transplantation. The NOD/SCID xenotransplant system provides the means to further clarify the processes underlying human stem cell engraftment.

Acute Disease↗

PubMed1999

Repeat tear of postoperative meniscus: potential MR imaging signs.

PURPOSE: To determine the usefulness of five magnetic resonance (MR) signs of repeat tears of the postoperative meniscus. MATERIALS AND METHODS: Fat-saturated proton-density-weighted and T2-weighted MR images in 20 patients who had undergone at least two knee surgeries were reviewed. Second-look arthroscopic confirmation of meniscal status was available in all patients. MR images of 39 menisci (10 repeat tears, 11 postoperative menisci without repeat tears, three tears in previously normal menisci, and 15 normal menisci) were evaluated for (a) a linear area of abnormal signal intensity extending to an articular surface on intermediate-weighted images, (b) abnormal meniscal morphology, (c) likelihood of a typical postoperative appearance, (d) fluid extending into the linear area on T2-weighted images, and (e) cartilage defects. Two radiologists rated their confidence on a five-point scale for the presence of these signs and were compared for level of agreement. RESULTS: The intraclass correlation coefficient (range, 0.75-0.91) indicated a high level of agreement. Areas under the receiver operating characteristic curves were large (range, 0.70-0.87) for all five signs, with a line (grade 3 signal intensity) and fluid within a line having the highest areas. These two signs also had the highest statistical scores (chi 2 = 14.12 and 13.30; P < .002; odds ratio, 1.588 and 1.599 for the line and the fluid within the line, respectively). CONCLUSION: The two best MR signs of repeat tear of the postoperative meniscus were the presence of a line and fluid within the line extending to an articular surface.

Adult↗

PubMed1999

Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini.

The mechanisms responsible for intrapancreatic digestive enzyme activation as well as the relationship between that activation and cell injury during pancreatitis are not understood. We have employed an in vitro system in which freshly prepared pancreatic acini are exposed to a supramaximally stimulating concentration of the CCK analog caerulein to explore these issues. We find that in vitro trypsinogen activation depends on the continued presence of Ca2+ in the suspending medium and that it is half-maximal in the presence of 0.3 mM Ca2+. Caerulein-induced trypsinogen activation can be halted by removal of Ca2+ from the suspending medium or by chelation of intracellular Ca2+. Increasing intracellular Ca2+ with either ionomycin or thapsigargin does not induce trypsinogen activation. We have monitored cell injury by measuring the leakage of lactate dehydrogenase (LDH) from acini and by quantitating intercalation of propidium iodide (PI) into DNA. Leakage of LDH and intercalation of PI in response to supramaximal stimulation with caerulein can be detected only after caerulein-induced trypsinogen activation has already occurred, and these indications of cell injury can be prevented by addition of a cell-permeant protease inhibitor. Our findings indicate that caerulein-induced intra-acinar cell activation of trypsinogen depends on a rise in intracellular Ca2+, which reflects entry of Ca2+ from the suspending medium. Intra-acinar cell activation of trypsinogen is an early as well as a critical event in pancreatitis. The subsequent cell injury in this model is mediated by activated proteases.

Animals↗

PubMed1999

Epilepsy surgery in India: All India Institute of Medical Sciences experience.

OBJECTIVES: Surgical treatment of epilepsy should be considered an important alternative to medical therapy. The identification of a suitable candidate, pre-operative evaluation requires a multidisciplinary team. The specific diagnostic studies required depend on the operative strategy and objective of surgical treatment. METHODS: In twenty patients with medically intractable epilepsy, who had clinical evaluation, electroencephalography (EEG), video-EEG monitoring using scalp electrodes, high resolution magnetic resonance imaging (MRI), neuropsychology, single photon emission computed tomography (SPECT) was done to localise the seizure focus. If the investigations were concordant resective surgery was performed. In case of frequent falls, atonic and tonic seizures, with generalised/multifocal discharges on EEG, a callostomy was done. Surgical outcome was assessed using Engel's 4 point scale. RESULTS: In 18 patients the seizure focus was localised, 13 had temporal lobectomy, five extra-temporal resection, and two had callosotomy. Fifteen patients had a follow-up of more than eight months, mean 20.5 (range 8-35 months), 13 had outcome I (seizure free), two had outcome II (occasional seizures), one-outcome III. Three were lost to follow-up and one patient died. There were no major post-operative complications. CONCLUSIONS: Surgical treatment of epilepsy is a safe, effective mode of therapy. Suitable candidates should be identified early and referred to appropriate centres.

Adolescent↗

PubMed1998

Treatment of non-obese diabetic (NOD)/Severe-combined immunodeficient mice (SCID) with flt3 ligand and interleukin-7 impairs the B-lineage commitment of repopulating cells after transplantation of human hematopoietic cells.

Until recently, the identification of cellular factors that govern the developmental program of human stem cells has been difficult due to the absence of repopulation assays that detect human stem cells. The transplantation of human bone marrow (BM) or cord blood (CB) into non-obese diabetic (NOD)/severe-combined immunodeficient (SCID) mice has enabled identification of primitive human cells capable of multilineage repopulation of NOD/SCID mice (termed the SCID-repopulating cell [SRC]). Here, we examined the effect of long-term in vivo treatment with various combinations of human cytokines on the developmental program of SRC. Detailed flow cytometric analysis of engrafted mice indicated that the vast majority of the human graft of untreated mice was comprised of B lymphocytes at various stages of development as well as myeloid and primitive cells; T cells were not reproducibly detected. Many studies, including murine in vitro and in vivo data and human in vitro experiments, have suggested that flt3 ligand (FL) and/or Interleukin-7 (IL-7) promotes T- and B-cell development. Unexpectedly, we found that treatment of engrafted mice with the FL/IL-7 combination did not induce human T- or B-cell development, but instead markedly reduced B-cell development with a concomitant shift in the lineage distribution towards the myeloid lineage. Effects on lineage distribution were similar in engrafted mice transplanted with highly purified cells indicating that the action of the cytokines was not via cotransplanted mature cells from CB or BM cells. These data show that the lineage development of the human graft in NOD/SCID mice can be modulated by administration of human cytokines providing a valuable tool to evaluate the in vivo action of human cytokines on human repopulating cells.

Animals↗

PubMed1998

Aldehyde reductase: the role of C-terminal residues in defining substrate and cofactor specificities.

The only major structural difference between aldehyde reductase, a primarily NADPH-dependent aldo-keto reductase, and aldose reductase, a dually coenzyme-specific (NADPH/NADH) member of the same superfamily, is an additional eight amino acid residues in the substrate/inhibitor binding site (C-terminal region) of aldehyde reductase. On the premise that this segment defines the substrate specificity of the enzyme, a mutant of aldehyde reductase lacking residues 306-313 was constructed. In contrast to wild-type enzyme, the mutant enzyme reduced a narrower range of aldehydes and the new substrate specificity was not similar to aldose reductase as might have been predicted. A major change in coenzyme specificity was observed, however, the mutant enzyme being distinctly NADH preferring(Km, NADH = 35 microM, compared to <5 mM for wild-type and Km, NADPH = 670 microM, compared to 35 microM for wild type). Upon analyzing coordinates of aldehyde and aldose reductase, we found that deletion of residues 306-313 may have created a truncated enzyme that retained the three-dimensional structural features of the enzyme's C-terminal segment. The change in substrate specificity could be explained by the new alignment of amino acids. The reversal of coenzyme specificity appeared to be due to a significant backbone shift initiated by the formation of a strong hydrogen bond between Tyr319 and Val300. A similar bond exists in aldose reductase (Tyr309-Ala299). It appears, therefore, that as far as coenzyme specificity is concerned, deletion of residues 306-313 has converted aldehyde reductase into an aldose reductase-like enzyme.

Aldehyde Reductase↗

PubMed1998

Induction of apoptosis in pancreatic acinar cells reduces the severity of acute pancreatitis.

1-Cyano-2-hydroxy-3-butene (CHB) has been reported to cause cell death in rat pancreatic acini. In this report, we describe the time-dependent effects of CHB on mouse acinar cell apoptosis and the effects of CHB-induced acinar cell apoptosis on the severity of secretagogue-induced acute pancreatitis in mice. CHB administration to mice resulted in a time-dependent increase in pancreatic apoptosis, which was maximal 12 hours after CHB administration. The severity of pancreatitis was significantly reduced by prior CHB administration and maximal protection was observed when the caerulein injections were started 12 hours after CHB administration. These observations indicate that induction of apoptosis can reduce the severity of pancreatitis and they suggest that induction of pancreatic acinar cell apoptosis may be beneficial in the clinical management of acute pancreatitis.

Acute Disease↗

PubMed1998

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury.

Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inflammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R-/- mice when compared with wild-type NK1R+/+ animals. Similarly, pancreatitis-associated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R-/- animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and pancreatitis-associated lung injury.

Acute Disease↗

PubMed1998

The effects of neutrophil depletion on a completely noninvasive model of acute pancreatitis-associated lung injury.

CONCLUSION: A completely noninvasive animal model of acute pancreatitis-associated lung injury was used to show that neutrophils, activated by pancreatitis, play a key role in mediating pancreatitis-associated lung injury. BACKGROUND: Significant pulmonary complications have been known to occur in over 50% of patients with severe acute pancreatitis. Recent studies using a variety of animal models of pancreatitis have suggested that neutrophil activation may play an important role in mediating lung injury. However, in these models, the interpretation of the results is complicated because surgical manipulations alone could have resulted in the activation of neutrophils. METHODS: Young female mice were fed a choline deficient ethionine (CDE) supplemented diet. The severity of pancreatitis was evaluated by measuring hyperamylasemia, acinar cell necrosis, and pancreatic myeloperoxidase activity. Lung injury was quantified by measuring lung microvascular permeability and lung myeloperoxidase activity. To evaluate the role of neutrophils in CDE diet-induced pancreatitis-associated lung injury, animals were pretreated with antineutrophil serum. RESULTS: Mice fed the CDE diet develop pancreatitis-associated lung injury. Pretreatment of mice with antineutrophil serum results in marked depletion of circulating neutrophils. Under these conditions, the severity of pancreatitis is reduced and lung injury is completely prevented.

Acute Disease↗

PubMed1998

Effect of recombinant platelet-activating factor acetylhydrolase on two models of experimental acute pancreatitis.

BACKGROUND & AIMS: Recent reports suggest that platelet-activating factor (PAF) plays a role in pancreatitis and pancreatitis-associated lung injury. In this study, the effects on these processes of termination of PAF action by recombinant PAF-acetylhydrolase (rPAF-AH) were investigated. METHODS: Rats were given rPAF-AH and then infused with a supramaximally stimulating dose of cerulein to induce mild pancreatitis. Opossums underwent biliopancreatic duct ligation to induce severe pancreatitis, and rPAF-AH administration was begun 2 days later. RESULTS: In mild, secretagogue-induced pancreatitis, rPAF-AH given before the cerulein reduced hyperamylasemia, acinar cell vacuolization, and pancreatic inflammation but did not alter pancreatic edema or pulmonary microvascular permeability. In severe, biliopancreatic duct ligation-induced pancreatitis, rPAF-AH delayed and reduced the extent of inflammation and acinar cell injury/necrosis and completely prevented lung injury even though the rPAF-AH administration was begun after the onset of pancreatitis. CONCLUSIONS: PAF plays an important role in the regulation of pancreatic injury but not pancreatic edema or increased pulmonary microvascular permeability in mild, secretagogue-induced pancreatitis. PAF plays a critical role in the regulation of progression of pancreatic injury and mediation of pancreatitis-associated lung injury in severe biliary pancreatitis. Amelioration of pancreatitis and prevention of pancreatitis-associated lung injury can be achieved with rPAF-AH even if treatment is begun after pancreatitis is established.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1998

A newly discovered class of human hematopoietic cells with SCID-repopulating activity.

The detection of primitive hematopoietic cells based on repopulation of immune-deficient mice is a powerful tool to characterize the human stem-cell compartment. Here, we identify a newly discovered human repopulating cell, distinct from previously identified repopulating cells, that initiates multilineage hematopoiesis in NOD/SCID mice. We call such cells CD34neg-SCID repopulating cells, or CD34neg-SRC. CD34neg-SRC are restricted to a Lin-CD34-CD38- population without detectable surface markers for multiple lineages and CD38 or those previously associated with stem cells (HLA-DR, Thy-1 and CD34). In contrast to CD34+ subfractions, Lin-CD34-CD38- cells have low clonogenicity in short-and long-term in vitro assays. The number of CD34neg-SRC increased in short-term suspension cultures in conditions that did not maintain SRC derived from CD34+ populations, providing independent biological evidence of their distinctiveness. The identification of this newly discovered cell demonstrates complexity of the organization of the human stem-cell compartment and has important implications for clinical applications involving stem-cell transplantation.

Animals↗

PubMed1998

Intra-acinar cell activation of trypsinogen during caerulein-induced pancreatitis in rats.

Supramaximal stimulation of the pancreas with the CCK analog caerulein causes acute edematous pancreatitis. In this model, active trypsin can be detected in the pancreas shortly after the start of supramaximal stimulation. Incubation of pancreatic acini in vitro with a supramaximally stimulating caerulein concentration also results in rapid activation of trypsinogen. In the current study, we have used the techniques of subcellular fractionation and both light and electron microscopy immunolocalization to identify the site of trypsinogen activation and the subsequent fate of trypsin during caerulein-induced pancreatitis. We report that trypsin activity and trypsinogen-activation peptide (TAP), which is released on activation of trypsinogen, are first detectable in a heavy subcellular fraction. This fraction is enriched in digestive enzyme zymogens and lysosomal hydrolases. Subsequent to trypsinogen activation, both trypsin activity and TAP move to a soluble compartment. Immunolocalization studies indicate that trypsinogen activation occurs in cytoplasmic vacuoles that contain the lysosomal hydrolase cathepsin B. These observations suggest that, during the early stages of pancreatitis, trypsinogen is activated in subcellular organelles containing colocalized digestive enzyme zymogens and lysosomal hydrolases and that, subsequent to its activation, trypsin is released into the cytosol.

Acute Disease↗

PubMed1997

Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury.

beta-Chemokines and their receptors mediate the trafficking and activation of a variety of leukocytes including the lymphocyte and macrophage. An array of no less than eight beta-chemokine receptors has been identified, four of which are capable of recognizing the chemokines MIP1alpha and RANTES. Genetic deletion of one of the MIP1alpha and RANTES receptors, CCR5, is associated with protection from infection with HIV-1 in humans, while deletion of the ligand MIP1alpha protects against Coxsackie virus-associated myocarditis. In this report we show that the deletion of another receptor for MIP1alpha and RANTES, the CCR1 receptor, is associated with protection from pulmonary inflammation secondary to acute pancreatitis in the mouse. The protection from lung injury is associated with decreased levels of TNF-alpha in a temporal sequence indicating that the activation of the CCR1 receptor is an early event in the systemic inflammatory response syndrome.

Animals↗

PubMed1997

Quantitative analysis reveals expansion of human hematopoietic repopulating cells after short-term ex vivo culture.

Ex vivo culture of human hematopoietic cells is a crucial component of many therapeutic applications. Although current culture conditions have been optimized using quantitative in vitro progenitor assays, knowledge of the conditions that permit maintenance of primitive human repopulating cells is lacking. We report that primitive human cells capable of repopulating nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice (SCID-repopulating cells; SRC) can be maintained and/or modestly increased after culture of CD34+CD38- cord blood cells in serum-free conditions. Quantitative analysis demonstrated a 4- and 10-fold increase in the number of CD34+CD38- cells and colony-forming cells, respectively, as well as a 2- to 4-fold increase in SRC after 4 d of culture. However, after 9 d of culture, all SRC were lost, despite further increases in total cells, CFC content, and CD34+ cells. These studies indicate that caution must be exercised in extending the duration of ex vivo cultures used for transplantation, and demonstrate the importance of the SRC assay in the development of culture conditions that support primitive cells.

ADP-ribosyl Cyclase↗