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At least 1,315 records · Page 73Linked to original sources
PubMed1999

Ionized prodrugs of dehydroepiandrosterone for transdermal iontophoretic delivery.

PURPOSE: The aim of this work was to synthesize ionized dehydroepiandrosterone (DHEA) prodrugs with higher water solubility, useful for iontophoretic transdermal application. METHODS: The synthesized derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Solid state and solution stability was also determined. Transdermal iontophoretic anodal transport in vitro was studied using excised rabbit skin. RESULTS: Two DHEA ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a quaternary ammonium salt. The two derivatives possess higher water solubility and lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to enzymatic hydrolysis; in particular the primary amine was hydrolyzed faster than the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of the two prodrugs was slightly higher than the parent drug. In the case of passive diffusion, only DHEA was found in the receptor compartment, indicating the complete breakdown of the prodrug in the skin. Current application gave higher drug flux and a significant amount of prodrug was found in the receptor. CONCLUSIONS: The use of ionized prodrugs of DHEA can increase the flux attainable during transdermal anodal iontophoresis by up to 7 times, but they are useful for passive transport as well.

Administration, Cutaneous↗
PubMed1999

Desorption-ionization mass spectrometry on porous silicon.

Desorption mass spectrometry has undergone significant improvements since the original experiments were performed more than 90 years ago. The most dramatic change occurred in the early 1980s with the introduction of an organic matrix to transfer energy to the analyte. This reduces ion fragmentation but also introduces background ions from the matrix. Here we describe a matrix-free strategy for biomolecular mass spectrometry based on pulsed-laser desorption-ionization from a porous silicon surface. Our method uses porous silicon to trap analytes deposited on the surface, and laser irradiation to vaporize and ionize them. We show that the method works at femtomole and attomole levels of analyte, and induces little or no fragmentation, in contrast to what is typically observed with other such approaches. The ability to perform these measurements without a matrix also makes it more amenable to small-molecule analysis. Chemical and structural modification of the porous silicon has enabled optimization of the ionization characteristics of the surface. Our technique offers good sensitivity as well as compatibility with silicon-based microfluidics and microchip technologies.

Mass Spectrometry↗
PubMed1996

Activation of Raf by ionizing radiation.

The critical pathways through which ionizing radiation induces malignant transformation and cell death are not well defined. Raf-1, a cytoplasmic serine-threonine protein kinase, mediates the transmission of mitogenic signals initiated at the cell membrane to the nucleus, resulting in the activation of transcription factors that regulate cell growth and proliferation. Moreover, Raf-1 overexpression and activation increases the survival response of mammalian cells to the toxic effects of ionizing radiation by an as-yet unknown mechanism (refs 3, 4 and V. Soldatenkov et al.; manuscript submitted). Somewhat analogous to mitogen-induced signalling, radiation stimulates protein-tyrosine kinase(s) and transcription factors. No direct biochemical link has been established, however, between radiation-stimulated protein tyrosine phosphorylation and downstream signals. Here we report a series of radiation-responsive events in which protein-tyrosine phosphorylation is followed by membrane recruitment, then tyrosine phosphorylation and activation of Raf-1 in vivo. Our results show that radiation-stimulated protein-tyrosine kinase(s) modify Raf-1, and implicate Raf-1 in the ionizing-radiation signal-transduction pathway.

Biological Transport↗
PubMed2003

Miniaturized gas ionization sensors using carbon nanotubes.

Gas sensors operate by a variety of fundamentally different mechanisms. Ionization sensors work by fingerprinting the ionization characteristics of distinct gases, but they are limited by their huge, bulky architecture, high power consumption and risky high-voltage operation. Here we report the fabrication and successful testing of ionization microsensors featuring the electrical breakdown of a range of gases and gas mixtures at carbon nanotube tips. The sharp tips of nanotubes generate very high electric fields at relatively low voltages, lowering breakdown voltages several-fold in comparison to traditional electrodes, and thereby enabling compact, battery-powered and safe operation of such sensors. The sensors show good sensitivity and selectivity, and are unaffected by extraneous factors such as temperature, humidity, and gas flow. As such, the devices offer several practical advantages over previously reported nanotube sensor systems. The simple, low-cost, sensors described here could be deployed for a variety of applications, such as environmental monitoring, sensing in chemical processing plants, and gas detection for counter-terrorism.

Air↗
PubMed2026

Charge-switching ionizable lipids lower the toxicity of lipid nanoparticles.

Lipid nanoparticles (LNPs) have great potential as nucleic acid delivery vehicles; however, they trigger the production of inflammatory cytokines, which limits their medical applications. Developing non-inflammatory LNPs is challenging because the LNP's ionizable lipid and the process of endosomal disruption are the major sources of LNP toxicity but are also essential for delivering nucleic acids. Here we demonstrate that ionizable lipids containing a carboxylic acid and an amine (termed S-lipid) switch their charged state between the pHs of 7.4 and 4.0, allowing them to generate LNPs (termed switchable nanoparticles) that efficiently encapsulate nucleic acid and trigger endosomal release without activation of the TLR4, complement, galectin-8 and platelet activating factor signalling pathways. Finally, we demonstrate that switchable nanoparticles are better at treating lipopolysaccharide-induced acute lung injury than traditional LNPs because they do not exacerbate pre-existing inflammation. Collectively, these results demonstrate that negatively charged ionizable lipids can mitigate the toxicity of LNPs.

Journal Article↗
PubMed2005

Combined ionizing radiation and sKDR gene delivery for treatment of prostate carcinomas.

Overexpression of vascular endothelial growth factor (VEGF) and its cognate receptor KDR has been linked to a more aggressive phenotype of human prostate carcinomas. The importance of signal transduction through the VEGF receptor 2 is illustrated by use of soluble KDR, which binds to VEGF and sequesters this ligand before its binding to cellular receptor. Treatment with recombinant adenovirus AdVEGF-sKDR, encoding sKDR under control of the human VEGF promoter, significantly inhibited the proliferation of human vascular endothelial cells and prostate cancer cells. AdVEGF-sKDR infection decreased migration of endothelial 1P-1B cells (61% reduction) and DU145 prostate carcinoma cells (47%) in comparison with AdCMV-Luc-infected control cells. Ionizing radiation upregulated VEGF promoter activity in prostate carcinoma and endothelial cells. AdVEGF-sKDR infection significantly reduced human vascular endothelial and prostate cancer cell proliferation and sensitized cancer cells to ionizing radiation. In vivo tumor therapy studies demonstrated significant inhibition of DU145 tumor growth in mice that received combined AdVEGF-sKDR infection and ionizing radiation versus AdVEGF-sKDR alone or radiation therapy alone. These results suggest that selective transcriptional targeting of sKDR gene expression employing a radiation inducible promoter can effectively inhibit tumor growth and demonstrate the advantage of combination radiotherapy and gene therapy for the treatment of prostate cancer.

Adenoviridae↗
PubMed2000

ATM-dependent phosphorylation and accumulation of endogenous BLM protein in response to ionizing radiation.

Bloom's syndrome (BS), a rare genetic disease, arises through mutations in both alleles of the BLM gene which encodes a 3'-5' DNA helicase identified as a member of the RecQ family. BS patients exhibit a high predisposition to development of all types of cancer affecting the general population and BLM-deficient cells display a strong genetic instability. We recently showed that BLM protein expression is regulated during the cell cycle, accumulating to high levels in S phase, persisting in G2/M and sharply declining in G1, suggesting a possible implication of BLM in a replication (S phase) and/or post-replication (G2 phase) process. Here we show that, in response to ionizing radiation, BLM-deficient cells exhibit a normal p53 response as well as an intact G1/S cell cycle checkpoint, which indicates that ATM and p53 pathways are functional in BS cells. We also show that the BLM defect is associated with a partial escape of cells from the gamma-irradiation-induced G2/M cell cycle checkpoint. Finally, we present data demonstrating that, in response to ionizing radiation, BLM protein is phosphorylated and accumulates through an ATM-dependent pathway. Altogether, our data indicate that BLM participates in the cellular response to ionizing radiation by acting as an ATM kinase downstream effector.

Adenosine Triphosphatases↗
PubMed2006

Ionizing radiation activates IGF-1R triggering a cytoprotective signaling by interfering with Ku-DNA binding and by modulating Ku86 expression via a p38 kinase-dependent mechanism.

Ionizing radiation exposure results in the activation of several tyrosine kinase receptors that participate in radiation-induced DNA damage response and radioresistance. We previously showed that insulin-like growth factor 1 receptor (IGF-1R) inhibition enhanced radiosensitivity of non-small-cell lung cancer (NSCLC) cells. In this paper, we demonstrate that in U1810 NSCLC cells gamma-radiation activates IGF-1R within 10 min, with a maximal activation effect 2 h post-irradiation. Impairment of IGF-1R tyrosine kinase activity enhances human lung cancer cells radiosensitivity by a mechanism that involves phosphatidylinositol 3-kinase (PI3-K) and p38 kinase. In an active form, IGF-1R binds and activates p38 kinase, promoting receptor signaling. Conversely, inhibition of IGF-1R phosphorylation results in IGF-1R/p38 complex disruption and p38 kinase inactivation. We have also demonstrated that in insulin-like growth factor-1-stimulated cells, Ku-DNA-binding activation is induced by ionizing radiation within 4 h, reaches a maximum level at 12 h and remains active up to 72 h. Blockade of IGF-1R activity or its downstream signaling through p38 kinase induces a decrease in radiation-mediated Ku-DNA-binding activation and downregulates the level of Ku86, without affecting Ku70 expression in the nucleus of U1810 cells. The IGF-1R signaling via PI3-K does not interfere with the p38 signaling, the Ku-DNA-binding activity or the level of Ku86. Our present study demonstrates for the first time that ionizing radiation activates IGF-1R. Inhibition of IGF-1R signaling via p38 kinase induces radiosensitivity by a novel mechanism involving nuclear Ku86.

Antigens, Nuclear↗
PubMed2005

Proton di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in cone, partial-cone and 1,3-alternate conformations: synthesis and alkaline earth metal cation extraction.

Novel proton di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in cone, partial-cone and 1,3-alternate conformations are synthesized to compare the efficiency and selectivity with which they extract alkaline earth metal ions. In these ligands, a crown-6 polyether unit links alternate aromatic rings of the calix[4]arene framework. To the remaining lower-rim positions are attached oxyacetic acid or N-(X)sulfonyl oxyacetamide groups. Changing the conformation varies the spatial relationship between a polyether-complexed divalent metal ion and the ionized side arms of the ligands. This is found to markedly affect the efficiency and selectivity in competitive solvent extraction of alkaline earth metal ions from aqueous solutions into chloroform by the di-ionizable calix[4]arene-crown-6 ligands.

Journal Article↗
PubMed2006

Synthesis and alkaline earth metal cation extraction by proton di-ionizable p-tert-butylcalix[4]arene-crown-5 compounds in cone, partial-cone and 1,3-alternate conformations.

Synthetic strategies for novel, proton di-ionizable p-tert-butylcalix[4]arene-crown-5 compounds in cone, partial-cone and 1,3-alternate conformations are reported. Selective linkage of the two diametrical phenolic oxygens in p-tert-butylcalix[4]arene with tetraethylene glycol ditosylate gave 1,3-bridged p-tert-butylcalix[4]arene-crown-5. The two remaining phenolic units were alkylated using NaH and KH as the bases to give the cone and partial-cone conformers, respectively. Preparation of the 1,3-alternate conformers utilized a different sequence in which O-alkylation was followed by crown ether ring formation. Structures of these new ligands were elucidated by (1)H and (13)C NMR spectroscopy. These proton-ionizable ligands were tested for their solvent extraction properties toward alkaline earth metal cations. Surprising differences in their extraction behaviors are noted compared to those reported previously for di-ionizable p-tert-butylcalix[4]arenecrown-6 analogues.

Journal Article↗
PubMed2006

Di-ionizable p-tert-butylcalix[4]arene-1,2-crown-5 and -crown-6 compounds in the cone conformation: synthesis and alkaline earth metal cation extraction.

Di-ionizable p-tert-butylcalix[4]arene-1,2-crown-5 and -crown-6 ethers in the cone conformation were prepared and their conformations and regioselectivities were verified by NMR spectroscopy. The metal ion-complexing properties of these ligands were evaluated by competitive solvent extractions of alkaline earth metal cations from water into chloroform. The ligands were found to be efficient extractants with selectivity for Ba(2+). The maximal loadings were 95-100% as calculated for formation of 1 : 1 ionized ligand-metal ion complexes. With the variation of proton-ionizable groups, which were oxyacetic acid moieties and N-(X)sulfonyl oxyacetamide units with X = methyl, phenyl, 4-nitrophenyl, and trifluoromethyl, "tunable" acidity was obtained.

Journal Article↗
PubMed1985

A 13C-n.m.r. investigation of ionizations within a trypsin-inhibitor complex. Evidence that the pKa of histidine-57 is raised by interaction with the hemiketal oxyanion.

The 13C-n.m.r. titration shifts of the alpha-methylene group of N-alkylated imidazoles are shown to be a sensitive probe of the ionization of the imidazolium ion. The 13C-n.m.r. titration shifts of both the intact and denatured/autolysed 2-13C- and 1-13C-enriched trypsin-7-amino-3-benzyloxycarbonylamino-1-chloroheptan-2-one (Z-Lys-CH2Cl) complexes are compared. The titration shift for the denatured/autolysed complex confirms that this ionization is due to deprotonation of the N-alkylated imidazolium ring of histidine-57. In the intact trypsin-inhibitor complex the titration shift due to the 1-13C-enriched carbon is anomalous. We conclude that this titration shift cannot arise solely from the ionization of the imidazolium ion of histidine-57 and that the pKa of the imidazolium ion of histidine-57 is raised in the trypsin-inhibitor complex. The relevance of these studies to the mechanism of action of the serine proteinases is discussed.

Alkylation↗
PubMed1992

A nucleotide receptor in vascular endothelial cells is specifically activated by the fully ionized forms of ATP and UTP.

Extracellular ATP causes an increase in the concentration of cytoplasmic free calcium ([Ca2+]i) in bovine pulmonary-artery endothelial (BPAE) cells that results in the synthesis and release of prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet aggregation. We show here that PGI2 release in BPAE cells correlates with the concentration of the fully ionized form of extracellular ATP (ATP4-) and not with the concentration of other ionic forms of ATP. Concentrations as low as 10 nM-ATP4- elicited an increase in PGI2 release [EC50 (concn. giving half-maximal stimulation) 3 microM] in BPAE cells incubated in an iso-osmotic medium, pH 7.4, lacking Ca2+ and Mg2+. When the pH or the Mg2+ concentration of the medium was varied so as to maintain a constant level of ATP4-, while varying the concentration of proton-ATP (HATP3-) or MgATP2- respectively, PGI2 release remained constant. An inhibitory effect of extracellular Mg2+ on PGI2 release could be attributed solely to a decrease in the concentration of ATP4-. In contrast with Mg2+, extracellular Ca2+ stimulated PGI2 release induced by ATP. Several results suggest that extracellular Ca2+ modulates PGI2 release by increasing Ca2+ uptake through an ATP(4-)-activated plasma-membrane channel. In BPAE cells incubated in Ca(2+)-free medium, ATP elicited a transient increase in [Ca2+]i that declined to the basal level within 60 s. In cells incubated in Ca(2+)-containing medium, ATP caused an increase in [Ca2+]i that had two components: a transient peak in [Ca2+]i (0-60 s) and a sustained increase in [Ca2+]i that was maintained for several minutes after ATP addition. Increasing the concentration of extracellular calcium from 0.25 mM to 10 mM had no effect on the transient rise in [Ca2+]i induced by ATP, but significantly enhanced the magnitude of the sustained increase in [Ca2+]i. Alterations in the magnitude of the sustained increase in [Ca2+]i would likely modulate PGI2 release, which was not complete until 2 min after ATP addition. Extracellular Ca2+ also stimulated PGI2 release induced by bradykinin. Bradykinin caused a sustained increase in [Ca2+]i in BPAE cells in the presence of extracellular Ca2+. Finally, the magnitude of PGI2 release induced by UTP, a more potent agonist than ATP, correlated with the concentration of extracellular fully ionized UTP (UTP4-). These findings support the hypothesis that nucleotide receptors in BPAE cells recognize the fully ionized form of ATP and UTP and are coupled to signal-transduction pathways involving the mobilization of intracellular Ca2+, the influx of extracellular Ca2+ and the subsequent release of PGI2.

Adenosine Triphosphate↗
PubMed1993

Ionization characteristics of the Cys-25/His-159 interactive system and of the modulatory group of papain: resolution of ambiguity by electronic perturbation of the quasi-2-mercaptopyridine leaving group in a new pyrimidyl disulphide reactivity probe.

1. A new thiol-specific reactivity probe 4,4'-dipyrimidyl disulphide [compound (VII), m.p. 110 degrees C, pKa of its monohydronated form 0.91] was synthesized and used to resolve the ambiguity of interpretation of the behaviour of papain (EC 3.4.22.2) in alkaline media known to depend to varying extents on two ionizations with pKa values approx. 8.0-8.5 and > or = 9.5 respectively. 2. A new extensive pH-second-order rate constant (k) data set for the reaction of papain with 2-(acetamido)-ethyl 2'-pyridyl disulphide (IV) demonstrated the existence of a striking rate maximum at pH approx. 4, the independence of k around pH 8 and the increase in k with increase in pH across a pKa value of 10.0, behaviour similar to that of other 2-pyridyl disulphides (R-S-S-2-Py) that lack key substrate-like binding sites in R. 3. Although the simplest interpretation of the pKa value of 10.0 assigns it to the formation of (Cys-25)-S-/(His-159)-Im from the ion-pair state of the papain catalytic site, another interpretation may be conceived in which this pKa value is assigned to another group remote from the catalytic site, the state of ionization of which modulates catalytic-site behaviour. This alternative assignment is shown to require compensating effects in the pH region around 8 such that the formation of (Cys-25)-S-/(His-159)-Im across pKa 8.0-8.5 is without net kinetic effect in the reactions of simple 2-pyridyl disulphides such as compound (IV) and 2,2'-dipyridyl disulphide (II). 4. The lower basicity of compound (VII) relative to that of compound (II) (pKa 2.45) was predicted to diminish or abolish the compensation postulated as a possibility in reactions of 2-pyridyl disulphides because of the decreased effectiveness of reaction via a (His-159)-Im+H-assisted transition state. The characteristics of the pH-dependence of the reaction of papain with compound (VII) which are quite different from those for its reaction with compound (II) support both this prediction and the alternative assignment with a value of 8.3 for the pKa of the formation of (Cys-25)-S-/(His-159)-Im. 5. Evidence that the behaviour of papain towards both substrates and some substrate-derived time-dependent inhibitors is determined not only by the loss of the (Cys-25)-S-/(His-159)-Im+H ion-pair state by dehydronation with pKa 8.3 but also by another ionization of pKa approx. 10.0 is briefly discussed.

Binding Sites↗
PubMed1997

Platelet ionized magnesium, cyclic AMP, and cyclic GMP levels in migraine and tension-type headache.

Decreased serum and intracellular levels of magnesium have been reported in patients with migraine. It has been suggested that magnesium may play an important role in the attacks and pathogenesis of headaches. We measured ionized magnesium, cyclic AMP (adenosine monophosphate), and cyclic GMP (guanosine monophosphate) in platelets of patients with migraine, in patients with tension-type headache, and in healthy controls. The platelet level of ionized magnesium from patients with tension-type headache was significantly lower than the levels from the other two groups. The platelet level of cyclic AMP from patients with migraine was higher than those from the other groups. We found no significant differences in the platelet cyclic GMP levels among the three groups. It is suggested that reduced platelet ionized magnesium in patients with tension-type headache is related to abnormal platelet function, and that increased platelet cyclic AMP in patients with migraine is related to alteration of neurotransmitters in the platelet.

Adolescent↗
PubMedDate not supplied

An EDTA-associated anti-B agglutinin: the role of ionized calcium.

BACKGROUND: It is believed that EDTA-dependent panagglutination is associated with free carboxylic acids that support reactions of rare autoagglutinins. CASE REPORT: An ABO typing discrepancy occurred in an 88-year-old patient. The specificity of his autoagglutinin was demonstrated by panel cell study and absorption tests using normal donors' red cells or immunoadsorbents coated with A, B, or O substances. Inhibition assays were performed to determine whether the autoagglutinin was inhibited by ionized calcium or carboxylic acids. The autoagglutinin had anti-B specificity when tested in the presence of EDTA. It was neutralized by group B secretor saliva and adsorbed by crystalline silica coated with simple B substances with or without EDTA, although it was absorbed by group B red cells only in the presence of EDTA. The agglutinating activity was stronger at 25 degrees C (titer 64) than at 37 degrees C (titer 16) and was destroyed by treatment of the serum with dithiothreitol, which suggests that the autoagglutinin is IgM. This activity also appeared in the patient's serum after dialysis and in an eluate obtained after adsorption with simple B substances, and it was inhibited by the addition of CaCl2 at 0.5 mM or higher concentrations. This suggests that the agglutination is not dependent on EDTA but, rather, on the concentration of ionized calcium. The autoagglutinin failed to react with group B red cells treated with glutaraldehyde for 10 minutes. CONCLUSION: An anti-B autoagglutinin was shown to have caused an ABO typing discrepancy in the presence of EDTA. These results suggest that autoagglutination requires an environment with low levels of ionized calcium, but not the presence of carboxyl groups.

ABO Blood-Group System↗
PubMed2004

Dose-response relationship between plasma ionized calcium concentration and thrombelastography.

OBJECTIVES: To establish the threshold value for calcium at which coagulation commenced and to investigate the range over which changes in ionized calcium influenced coagulation. DESIGN: Controlled, nonblinded, in vitro observational study. SETTING: The study was conducted in a university-based laboratory. PARTICIPANTS: Blood was obtained from healthy volunteers. INTERVENTIONS: One hundred samples of citrated blood were recalcified using varying quantities of 10% calcium chloride solution. Heparinized samples from the recalcified blood were obtained for measurement of ionized calcium concentration (Ca(2+)). MEASUREMENTS AND RESULTS: Coagulation of the recalcified samples was analyzed using thrombelastography. The ionized calcium concentration in recalcified blood was measured using a calcium electrode in a blood gas analyzer. No sample with a Ca(2+) < 0.33 mmol/L showed any clot formation. Normal coagulation measures were obtained in almost all samples in which the Ca(2+) was >0.56 mmol/L. Final clot strength appeared to be independent of Ca(2+) once the threshold value of 0.33 mmol/L was exceeded. CONCLUSIONS: Ca(2+) of <0.33 mmol/L is necessary to prevent coagulation. Ca(2+) > 0.56 is unlikely to be the cause of coagulation abnormalities during surgical procedures in which calcium metabolism is deranged. Between these values, Ca(2+) may exert an effect on the rate of clot formation, but final clot strength should be unaffected.

Blood Coagulation↗
PubMed1996

Repair of DNA Damage Produced by Ionizing Radiation: A Minireview.

A knowledge of the biochemical and molecular basis of sensitivity to ionizing radiation can provide useful information regarding carcinogenesis, cancer susceptibility, and patient responses to radiotherapy. Various factors can influence radiosensitivity, including the induction, processing and manifestation of DNA damage. One factor known to strongly affect radiosensitivity is the ability of cells to repair damage to their DNA. Cells have evolved an elaborate array of enzymatic systems to maintain the integrity of their genetic material in the face of numerous agents that alter DNA structure or base sequence. Cellular repair of a macromolecule is known to occur only for DNA. In no other instance is the integrity of a single molecule so vital for the survival of a cell. A number of distinct enzymatic mechanisms are known that result in either the removal of damaged DNA bases or the rejoining of single- and double-strand breaks. In this article, we discuss some of the different types of DNA damage induced by ionizing radiation, including modified bases, sugar damage, strand breaks, and clustered DNA damage. This will be followed by a description of some of the basic mechanisms the cell uses to repair ionizing radiation-induced DNA damage, such as base excision repair. We will also discuss the relationship between DNA repair and other cellular processes, including transcription and the cell cycle. Recent advances, including the cloning and characterization of DNA repair genes implicated in human inherited disease, have provided new insights into the surprising complexity of cellular responses to DNA damage. Finally, the potential for using this information clinically will be discussed. The goal of this review is to inform the clinician not only about recent progress in the field of DNA repair, but also about relationships between the processing of DNA damage and other cellular functions.

Journal Article↗