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PubMed1999

Tissue-specific regulation of glutathione homeostasis and the activator protein-1 (AP-1) response in the rat conceptus.

Oxidative stress in the conceptus is characterized by an increased oxidized to reduced glutathione (GSSG:GSH) ratio and the induction of fos and jun mRNAs, transcripts for components of the activator protein-1 (AP-1) transcription factor. We investigated the role of glutathione homeostasis in the rat conceptus in the regulation of: (1) AP-1 expression and activity, and (2) the activities of glutathione-dependent cytoprotective enzymes. Glutathione content was enhanced with the addition of l-2-oxothiazolidine-4-carboxylate (OTC), a precursor of cysteine, a rate-limiting substrate in glutathione biosynthesis. Day 10 rat conceptuses were cultured for 44 hr with 0, 5, 10, or 20 mM OTC. High concentrations (10 and 20 mM) of OTC were embryotoxic. Incubation of the conceptus in 5 mM OTC caused mild (not statistically significant) embryotoxicity, increased significantly the embryonic glutathione content, prevented culture-induced oxidative stress, and inhibited the induction of AP-1 transcripts and DNA binding activity in the embryo. In contrast, in the yolk sac, 5 mM OTC failed to increase glutathione content or to prevent oxidative stress or AP-1 induction. Thus, regulation of glutathione status in the conceptus is tissue-specific. Glutathione S-transferase and glutathione peroxidase activities were increased approximately 50% in cultured embryos and yolk sacs. OTC treatment (5 mM) prevented this induction in the embryo, but not in the yolk sac, suggesting a role for glutathione homeostasis in the regulation of these enzymes. Tissue-specific regulation of glutathione status and of cytoprotective enzymes in the conceptus during organogenesis may impact on the consequences of insult with oxidative stress.

Animals↗
PubMed1999

Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides.

Proproteins and prohormones are the fundamental units from which bioactive proteins and peptides as well as neuropeptides are derived by limited proteolysis within the secretory pathway. Precursors are usually cleaved at the general motif (K/R)--(X)n--(K/R)down arrow, where n=0, 2, 4 or 6 and X is any amino acid and usually is not a Cys. Seven mammalian precursor convertases (PCs) have been identified: PC1, PC2, furin, PC4, PC5, PACE4 and PC7. Each of these enzymes, either alone or in combination with others, is responsible for the tissue-specific processing of multiple polypeptide precursors both in the brain and in periphery. This combinatorial mechanism generates a large diversity of bioactive molecules in an exquisitively regulated manner. The production of null mice allowed the assessment of the critical role of convertases in vivo. Thus, male PC4 (-/-) mice are infertile, furin (-/-) and PC1(-/-) mice are embryonic lethal, and PC2 (-/-) mice are mildly diabetic and runted. Interestingly, animals deficient in 7B2, a PC2-specific binding protein, exhibit a Cushing-like syndrome and die soon after birth. Recently, the first member of a new class of subtilisin--kexin-like convertases, called SKI-1, was identified. Its structure is closer to pyrolysin than to mammalian PCs and it exhibits a specificity for cleavage at the motif (R/K)--X--X--(L,T) down arrow as deduced from its ability to process sterol regulatory element binding proteins and pro-brain derived neurotrophic factor. Thus, while PCs are responsible for the processing of neuropeptides, adhesion molecules, receptors, growth factors, cell surface glycoprotein and enzymes, SKI-1 cleaves proproteins that are critical for the control of cholesterol and fatty acid metabolism and for neuronal protection and growth.

Amino Acid Sequence↗
PubMed2002

Growth and isotopic labelling of adherent cells in small volumes of medium.

The in vivo labelling of viral or cellular components is usually conducted through the addition of radioactively labelled precursors to the culture medium. A limiting factor for isotope use is often the cost of isotope purchase and disposal. Therefore, significant savings can be achieved if the smallest possible volume of medium is employed. However, in the case of adherent cells growing in tissue culture dishes or multi-well plates, surface tension causes a very uneven distribution of the liquid due to the formation of a meniscus at the edge of the petri. This prevents the use of very small volumes of medium for cell growth and labelling because the cells at the center of the petri dish would dry out and die, especially after longer incubation periods. In this communication, we describe a technique whereby cells are grown in an area surrounded by a hydrophobic ring of Teflon, which greatly improves the distribution of the medium by eliminating the concave meniscus. This translates into a dramatic improvement in the condition of the cells, as well as the efficiency of labelling of phosphoproteins, such as the Simian Virus 40 large tumor antigen with 32P-orthophosphate or labelling of the cellular DNA with 3[H]thymidine. The technique is useful for any application where growth of cells in small volumes of medium is required.

Animals↗
PubMed1997

Cholesterol metabolism and non-cholesterol sterols in patients with ileal pouch anastomosis.

BACKGROUND: Previous studies suggest only minor changes in bile acid metabolism after panproctocolectomy with ileal pouch construction. AIMS/METHODS: To investigate these changes further, we studied cholesterol absorption and serum, biliary and fecal non-cholesterol sterols and lipids in 12 ileal pouch patients and 10 controls. RESULTS: In patients, cholesterol absorption was markedly reduced and was associated with low serum total and LDL cholesterol and LDL triglyceride levels, but surprisingly, cholesterol synthesis, as indicated by sterol-balance data or serum cholesterol precursor levels, was within low normal limits. The high proportions of serum plant sterol to cholesterol, particularly that of campesterol, were not related to cholesterol absorption, but were attributable to a markedly reduced biliary cholesterol secretion. Interestingly, in these patients the fractional absorption of campesterol was normal, whereas that of sitosterol, like cholesterol, was reduced and was positively related to the intestinal influx of cholesterol. The patients' serum cholestanol proportion was normal, but the proportion of the cholestanol formed during intestinal passage was significantly reduced (17.9% vs 65.2% in controls). CONCLUSIONS: Thus ileal pouch patients are characterized by sterol malabsorption, lowered serum total and LDL-cholesterol levels, but unexpectedly without any increase in cholesterol synthesis. The lack of high serum cholestanol, shown earlier frequently in unoperated patients with ulcerative colitis, may indicate reversible cholestasis, a finding deserving further exploration.

Bile↗
PubMed2002

Use of an adenoviral vector to express soluble donor-major histocompatibility complex molecules capable of suppressing the immune response in rat transplant recipients.

There is an accumulating body of evidence indicating that soluble major histocompatibility complex (sMHC) molecules have donor-specific immunosuppressive properties. One classic, but still unproven, theory is that production of sMHC by liver transplants induces a potent immunosuppressive effect. To mimic this possible effect, we have developed a replication deficient adenovirus (Ad-RQ) to express high levels of donor sMHC class I molecules (sRT1.A(a)) in the liver. Ad-RQ produced sRT1.A(a) was measured by enzyme-linked immunosorbent assay (ELISA) after in vitro infection of Lewis (RT1(l)) hepatocytes, and in vivo following intravenous virus injection into Lewis rats. Results indicated high sRT1.A(a) expression in Lewis hepatocyte cultures and, in vivo, high expression was also demonstrated and maintained for at least 1 week. A strong immunosuppressive potential of sMHC in vivo was revealed by prolongation of cardiac (ACI, RT1(a)) heart allograft survival in high-responder Lewis rat recipients treated with Ad-RQ alone. Furthermore, limiting dilution cytotoxic T-lymphocyte precursor (CTLp) analysis of lymphocytes from Ad-RQ-treated Lewis recipients receiving an ACI heart transplant indicated a marked decrease in antidonor CTLp frequency. In conclusion, our results demonstrate that viral vectors can be used effectively to express high levels of sMHC molecules, and their immunosuppressive effect, without concurrent immunosuppression, is sufficiently potent to prolong heart transplant survival.

Adenoviridae↗
PubMed1999

Involvement of calcineurin in the signal transduction of PBAN in the silkworm, Bombyx mori (Lepidoptera).

In several moth species sex pheromone production in the pheromone gland is regulated by a neurohormone, pheromone biosynthesis activating neuropeptide (PBAN). In Bombyx mori it is suggested that PBAN, after binding to the cell-surface receptor, primarily activates a plasma membrane receptor-activated Ca2+ channel to increase cytosolic levels of Ca2+, and Ca2+/calmodulin complex directly or indirectly activates a phosphoprotein phosphatase, which in turn elicits activation of acyl CoA reductase (the key enzyme under PBAN control) through dephosphorylation, resulting in pheromone (bombykol) production. The effect of cyclosporin A (CsA) and FK 506, specific inhibitors of calcineurin (phosphoprotein phosphatase 2B) was studied on the sex pheromone production, in B. mori. The in vitro experiments showed that both chemicals exerted a dose-dependent inhibitory action when they were co-incubated with TKYFSPRL amide (Hez-PBAN fragment peptide). Practically, no difference was detected between the two chemicals in the tested doses (0.025-1250 microM). When effects of CsA or FK 506 were studied on cell-free production of bombykol by using microsomal fraction no inhibition was detected. Since microsomal fraction contains the acyl CoA synthetase, the rate-limiting acyl CoA reductase and the precursor, bombykol is produced if supplied with CoA, ATP and NADPH. Thus, the inhibitory action of CsA and FK506 under in vitro conditions should occur before the step of acyl group reduction and the effect is likely to be attributable to the inhibition of calcineurin in the signal transduction cascade mechanism of PBAN, in B. mori. The existence of calcineurin in the pheromone gland by using Western blot analysis is also demonstrated.

Animals↗
PubMed1997

Dissociation energetics and mechanisms of leucine enkephalin (M + H)+ and (2M + X)+ ions (X = H, Li, Na, K, and Rb) measured by blackbody infrared radiative dissociation.

The dissociation kinetics of protonated leucine enkephalin and its proton and alkali metal bound dimers were investigated by blackbody infrared radiative dissociation in a Fourier-transform mass spectrometer. From the temperature dependence of the unimolecular dissociation rate constants, Arrhenius activation parameters in the zero-pressure limit are obtained. Protonated leucine enkephalin dissociates to form b(4) and (M-H(2)O)(+) ions with an average activation energy (E(a)) of 1.1 eV and an A factor of 10(10.5) s(-1). The value of the A factor indicates that these dissociation processes are rearrangements. The b(4) ions subsequently dissociate to form a(4) ions via a process with a relatively high activation energy (1.3 eV), but one that is entropically favored. For the cationized dimers, the thermal stability decreases with increasing cation size, consistent with a simple electrostatic interaction in these noncovalent ion-molecule complexes. The E(a) and A factors are indistinguishable within experimental error with values of approximately 1.5 eV and 10(17) s(-1), respectively. Although not conclusive, results from master equation modeling indicate that all these BIRD processes, except for b(4) --> a(4), are in the rapid energy exchange limit. In this limit, the internal energy of the precursor ion population is given by a Boltzmann distribution and information about the energetics and dynamics of the reaction are obtained directly from the measured Arrhenius parameters.

Journal Article↗
PubMedDate not supplied

Enhancing the atom economy of polyketide biosynthetic processes through metabolic engineering.

Polyketides, a large family of bioactive natural products, are synthesized from building blocks derived from alpha-carboxylated Coenzyme A thioesters such as malonyl-CoA and (2S)-methylmalonyl-CoA. The productivity of polyketide fermentation processes in natural and heterologous hosts is frequently limited by the availability of these precursors in vivo. We describe a metabolic engineering strategy to enhance both the yield and volumetric productivity of polyketide biosynthesis. The genes matB and matC from Rhizobium trifolii encode a malonyl-CoA synthetase and a putative dicarboxylate transport protein, respectively. These proteins can directly convert exogenous malonate and methylmalonate into their corresponding CoA thioesters with an ATP requirement of 2 mol per mol of acyl-CoA produced. Heterologous expression of matBC in a recombinant strain of Streptomyces coelicolor that produces the macrolactone 6-deoxyerythronolide B results in a 300% enhancement of macrolactone titers. The unusual efficiency of the bioconversion is illustrated by the fact that approximately one-third of the methylmalonate units added to the fermentation medium are converted into macrolactones. The direct conversion of inexpensive feedstocks such as malonate and methylmalonate into polyketides represents the most carbon- and energy-efficient route to these high value natural products and has implications for cost-effective fermentation of numerous commercial and development-stage small molecules.

Acyl Coenzyme A↗
PubMedDate not supplied

Arabinose-induction of lac-derived promoter systems for penicillin acylase production in Escherichia coli.

Arabinose was shown to serve as an effective inducer for induction of the lac-derived promoters in Escherichia coli using penicillin acylase (PAC) as a model protein. Upon the induction with a conventional inducer, isopropyl-beta-d-thiogalactopyranoside (IPTG), for pac overexpression, which is regulated by the trc or (DE3)/T7 promoter, the production of PAC was limited by the accumulation of PAC precursors (proPAC) as inclusion bodies. Negative cellular responses, such as growth inhibition and cell lysis, were frequently observed, resulting in a low pac expression level and poor culture performance. Interestingly, these technical hurdles can be overcome simply through the use of arabinose as an inducer. The results indicate that arabinose not only induced the lac-derived promoter systems (i.e., trc and (DE3)/T7) for pac (or LL pac) overexpression but also facilitated the posttranslational processing of proPAC for maturation. However, the arabinose-inducibility appears to be host-dependent and becomes less observable in the strains with a mutation in the ara operon. The arabinose-inducibility was also investigated in the expression system with the coexistence of the trc promoter system regulating pac expression and another arabinose-inducible promoter system of araB regulating degP coexpression.

Arabinose↗
PubMed1989

Developmental regulation of stage-specific ribosome populations in Plasmodium.

The Plasmodium parasites are so far unique in biology in possessing developmentally regulated ribosomal RNA gene units. Two different genes encode their small subunit rRNAs: one gene (A) yields transcripts predominant in the asexual blood-stage parasites, and the other (C) is mainly transcribed in the sporozoite forms that develop in the mosquito. Developmental control of events allowing a switch in the complement of ribosomes must coordinate the production of the new class with selective inactivation and removal of the old. We show here that in P. falciparum the switch, from A to C gene expression involves the control of rRNA processing, allowing accumulation of precursor C-gene transcripts in gametocytes. These precursor molecules are processed to mature size in the zygote and the early ookinete, where both transcription and processing of the C-gene rRNA seem to be accelerated. As the C-gene precursor rRNA appears, a defined and limited pattern of breakdown of the dominant A-gene rRNA occurs, in which conserved, functionally active sequences involved in the termination of translation and elongation are targeted. By the late oocyst stage, the A-gene transcripts are virtually replaced by mature C-gene transcripts.

Animals↗
PubMed2003

Umbilical cord blood: the role of apoptosis in the control of CD34+ cell counts.

BACKGROUND AND OBJECTIVE: Cord blood obtained at delivery can be used for hematopoietic precursor cells (HPC) transplantation. The major limit for its success is represented by the low cellular yield of the stem cell population. The objective of this study was to determine the role played by apoptosis in the numerical control of CD34+ cell counts. DESIGN AND METHODS: Umbilical cord blood samples were collected from 15 women at the time of the delivery and cord blood units processed. Cells, collected following 24h and 48h of incubation, were analysed by flow cytometry using the gating strategy. RESULTS: Remarkable levels of apoptosis were detected in the stem cell population and a significant difference between apoptosis mean values at 24h and 48h within CD34+ cells were found. The difference between the percentage of apoptosis in CD34+ cells and that in the remaining population was significant both at 24h and at 48h. CONCLUSIONS: CD34+ cells have a higher likelihood to undergo apoptosis in comparison to the remaining ones present in umbilical cord blood. This process of cellular death plays a major role in the control of CD34+ cell counts in placental blood and influence, for this reason, the possibility of success of a cord blood transplantation.

Adult↗
PubMed1984

Cloning and sequencing of liver cDNA coding for bovine protein C.

cDNA coding for protein C has been cloned from a bovine liver library in plasmid vector pBR322 and its sequence has been determined. Two overlapping clones code for the entire light and heavy chains of the mature protein, as well as a previously unreported connecting dipeptide (Lys-Arg) and a 39-amino acid leader peptide region. Identification and characterization of the clones establishes the liver as a site of protein C biosynthesis. A contiguous coding region reveals that a one-chain precursor protein is made that upon limited proteolysis yields both the mature light and heavy chains. The codon for aspartic acid is found at light chain amino acid position 71, showing that the beta-hydroxyaspartic acid that exists in this position of the mature protein is the result of post-translational modification of an aspartic acid residue. Amino acid sequence homology in the amino-terminal region of the light chain with other vitamin K-dependent coagulation factors is continued into the leader peptide region.

Amino Acid Sequence↗
PubMed1989

Expression of the neutrophil elastase gene during human bone marrow cell differentiation.

Neutrophil elastase, a potent serine protease carried and released by activated neutrophils, is not synthesized by neutrophils, but by their bone marrow precursor cells. Using in situ hybridization with 35S-labeled antisense and sense neutrophil elastase cRNA probes, the present study demonstrates that expression of the neutrophil elastase gene is tightly controlled in bone marrow precursors and occurs during a very limited stage of differentiation of the neutrophil myeloid series, almost entirely at the promyelocyte stage. Neutrophil elastase mRNA transcript levels are detectable to a limited extent in blasts, increase markedly in the promyelocyte stage, and then disappear as promyelocytes further differentiate. Control probes specific for myeloperoxidase, lactoferrin, and beta-globin mRNA transcripts, respectively, demonstrated contrasting gene expression. Myeloperoxidase mRNA transcripts were also found almost exclusively at the promyelocyte stage, but myeloperoxidase mRNA levels disappeared earlier than do neutrophil elastase mRNA levels, suggesting that expression of these genes may be differently controlled. In comparison, lactoferrin mRNA transcripts were detected late in the neutrophil lineage, while beta-globin mRNA was detected only in cells of the erythroid lineage. Together these observations suggest that the expression of the neutrophil elastase gene is likely under very tight control, and is likely different than that for other constituents of the neutrophil granules.

Bone Marrow Cells↗
PubMed1993

High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response.

Polyclonal stimulation of CD8+ cytotoxic T lymphocytes (CTL) occurs during infection with many viruses including those not known to transform CTL or encode superantigens. This polyclonal CTL response includes the generation of high levels of allospecific CTL directed against many class I haplotypes. In this report we investigated whether the allospecific CTL generated during an acute lymphocytic choriomeningitis virus (LCMV) infection of C57BL/6 mice were stimulated specifically by antigen recognition or nonspecifically by polyclonal mechanisms possibly involving lymphokines or superantigens. An examination of the ability of different strains of mice to induce high levels of CTL specific for a given alloantigen showed that most, but not all, strains generated high levels of allospecific CTL, and that their abilities to generate them mapped genetically to the major histocompatibility complex locus, exclusive of the class II region. This indicated that the virus-induced allospecific CTL generation was independent of the class II allotype, and mice depleted of CD4+ cells generated allospecific CTL, indicating independence of class II-CD4+ cell interactions and resulting CD4+ cell-secreted lymphokines. FACS staining with a variety of V beta-binding antibodies did not show a superantigen-like depletion or enrichment of any tested V beta + subset during infection. Several experiments provided evidence in support of direct stimulation of CD8+ cells via the T cell receptor: (a) both virus- and allo-specific killing were enriched within a given V beta subpopulation; (b) relative CTL precursor frequencies against different class I alloantigens changed during the course of virus infection; (c) the relative levels of virus-induced, allospecific CTL-mediated lysis at day 8 after infection did not parallel the CTL precursor frequencies before infection; and (d) limiting dilution analyses of day 8 LCMV-infected spleen cells stimulated by virus-infected syngeneic peritoneal exudate cells (PEC) revealed not only the expected virus-specific CTL clones, but also a high frequency of clones that were cross-reactive with allogeneic and virus-infected syngeneic targets. In addition to the virus cross-reactive allospecific CTL clones, virus-infected PEC also stimulated the generation of some allospecific clones that did not lyse virus-infected fibroblasts. Surprisingly, LCMV-infected PEC were much more efficient at stimulating allospecific CTL clones from day 8 LCMV-infected splenocytes than were allogeneic stimulators. These results indicate that at least part of the polyclonal allospecific CTL response elicited by acute virus infection is a consequence of the selective expansion of many clones of allospecific CTL which cross-react with virus-infected cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Inhibition of interleukin 7 receptor signaling by antigen receptor assembly.

After the productive rearrangement of immunoglobulin (Ig) heavy chain genes, precursor (pre-)B lymphocytes undergo a limited number of cell divisions in response to interleukin (IL)-7. Here, we present evidence that this phase of IL-7-dependent expansion is constrained by an inhibitory signal initiated by antigen receptor assembly. A line of pre-B cells from normal murine bone marrow that expresses a mu heavy chain with a D-proximal V(H)7183.2 region divides continuously in IL-7. IL-7 responsiveness ceases upon differentiation to the mu(1), kappa(1) stage, despite continuing expression of the IL-7 receptor (IL-7R), suggesting that antigen receptor assembly inhibits IL-7 responsiveness. This is confirmed by introduction of a rearranged lambda light chain gene, which inhibits proliferative signaling through the IL-7R. Inhibition is specific to the IL-7R, because it is overcome by replacement of the IL-7R cytoplasmic domain with corresponding sequences from the closely related IL-2Rbeta chain. Alteration of a single tyrosine residue, Tyr410, in the IL-7R cytoplasmic domain to phenylalanine also prevents the inhibition of proliferation after antigen receptor assembly. Thus, the loss of IL-7 responsiveness after antigen receptor assembly may be mediated through the recruitment of an inhibitory molecule to this residue. Our findings identify a novel mechanism that limits cytokine-dependent proliferation during B lymphopoiesis. This mechanism may be essential for the proper regulation of peripheral B lymphocyte numbers.

Animals↗
PubMed2002

Memory cytotoxic T cell responses to viral tegument and regulatory proteins encoded by open reading frames 4, 10, 29, and 62 of varicella-zoster virus.

Cytotoxic T cell recognition of tegument and regulatory proteins encoded by open reading frames (ORFs) 4, 10, 29, and 62 of varicella-zoster virus (VZV) was evaluated using limiting dilution conditions to estimate the precursor frequencies of memory T cells specific for these proteins in immune subjects. Responder cell frequencies for ORFs 4, 10, and 62 gene products, which are virion tegument components and function as immediate early viral transactivating proteins, were equivalent. CTLp recognition of VZV proteins made in latently infected cells, which include ORF4 and ORF62 proteins, was not maintained preferentially when compared to ORF10 protein, which has not been shown to be expressed during latency. T cell recognition of ORF29 protein, the major DNA binding protein, which is expressed during replication but not incorporated into the virion tegument, was less common than responses to ORFs 4, 10, and 62 gene products. Older individuals had diminished numbers of memory CTLp that lysed autologous targets expressing IE62 protein; these responses were increased after immunization with live attenuated varicella vaccine to the range observed in younger adults. Adaptive immunity to VZV is characterized by a broad repertoire of memory CTL responses to proteins that comprise the virion tegument and regulate viral gene expression in infected cells.

Adult↗
PubMed1991

Propofol as an i.v. anaesthetic induction agent in variegate porphyria.

The choice of an i.v. anaesthetic induction poses problems for the anaesthetist confronted with a patient with one of the acute porphyrias. We undertook a prospective clinical trial in 13 variegate porphyric subjects using propofol as an anaesthetic induction agent. Urinary porphyrin precursors and porphyrins were measured before operation and 1-5 days after operation. Stool and plasma porphyrin concentrations were measured over the same period. Comparison of these data in the porphyric patients and in 21 control subjects over the trial period revealed no significant change in porphyrin or porphyrin precursor output after operation. Urinary porphyrin precursor concentrations did not exceed the limits established for variegate porphyric patients in remission, and there were no changes in the stool and plasma porphyrin profiles or any symptoms of an acute porphyric attack. We conclude that propofol did not appear to be porphyrinogenic when used for the induction of anaesthesia in 13 patients with variegate porphyria.

Adolescent↗
PubMed1984

Pyrimidine nucleotide metabolism in cardiac hypertrophy.

Cardiac hypertrophy was induced in rats either by isoprenaline treatment or by experimental abdominal aortic stenosis. In both models, the UTP content increased in the hypertrophying heart, while the ATP level remained depressed. The rate of net synthesis of uracil nucleotides, estimated by phosphate incorporation into alpha-phosphate groups, was largely increased during the first stage of hypertrophy (X 3.6 and 2.6, respectively). At identical stages of hypertrophy, the rate of synthesis of ribosomal RNA, measured after continuous intracardiac infusion of 3H-uridine, was increased by 1.6 and 2.5 times. A comparison of the changes in time course of the levels of UTP and RNA and their turnover suggests that the metabolism of uracil nucleotides and that of ribosomal RNA are closely interrelated. The increase in the rate of synthesis of pyrimidine is interpreted as an adaptational change in nucleotide metabolism in response to the increased requirement of precursors for RNA synthesis. The possible limiting role of pyrimidine nucleotides in the hypertrophic process is discussed.

Adenosine Triphosphate↗