Sodium Independent Sulfate Anion Transporter
Background
Section titled “Background”Sulfate is a crucial inorganic anion involved in a wide array of physiological processes, including the detoxification of xenobiotics, the biosynthesis of essential macromolecules like glycosaminoglycans and proteoglycans vital for connective tissue, and the sulfation of hormones and neurotransmitters. Maintaining appropriate sulfate levels within cells and body fluids is therefore essential for human health. Sodium independent sulfate anion transporters are a class of membrane proteins responsible for moving sulfate ions across cell membranes without directly relying on the sodium gradient.[1] These transporters play a critical role in sulfate homeostasis, ensuring its availability where needed and facilitating its elimination when in excess. [1]
Biological Basis
Section titled “Biological Basis”Sodium independent sulfate anion transporters are typically found embedded in the lipid bilayer of cells, where they facilitate the passage of sulfate ions. Their mechanism often involves anion exchange, where an inward movement of sulfate is coupled with the outward movement of another anion, or facilitated diffusion, where sulfate moves down its electrochemical gradient.[1] These transporters are widely expressed throughout the body, with significant roles in organs such as the kidneys, intestines, liver, and brain. In the kidneys, they are vital for the reabsorption of sulfate from the filtrate, preventing excessive loss from the body. In cartilage, they ensure sufficient sulfate uptake for the synthesis of sulfated proteoglycans, which are critical for the tissue’s structural integrity and function. [1]
Clinical Relevance
Section titled “Clinical Relevance”Dysfunction or genetic variations in sodium independent sulfate anion transporters can lead to a range of clinical conditions due to impaired sulfate metabolism. For instance, defects can result in disorders characterized by sulfate deficiency, affecting processes like detoxification, growth, and the development of connective tissues, potentially leading to skeletal abnormalities or metabolic imbalances. Conversely, issues leading to sulfate accumulation can also be detrimental. Understanding the function of these transporters is crucial for diagnosing and managing conditions where sulfate transport is compromised, as their activity directly impacts overall physiological health.[1]
Social Importance
Section titled “Social Importance”The widespread involvement of sulfate in numerous metabolic pathways underscores the social importance of understanding sodium independent sulfate anion transporters. Research into these transporters can lead to improved diagnostic tools and therapeutic strategies for a variety of conditions, ranging from rare genetic disorders affecting cartilage and bone development to more common issues related to detoxification and nutrient metabolism. Insights into their function can also contribute to personalized medicine, helping to explain individual variations in drug metabolism and susceptibility to environmental toxins, ultimately enhancing public health outcomes and quality of life.[1]
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Studies investigating genetic associations with traits, such as those related to a sodium independent sulfate anion transporter, often face inherent methodological and statistical limitations. The use of older or less dense SNP arrays, such as 100K arrays, may result in insufficient coverage of gene regions, potentially leading to missed true associations that could be identified with newer, more comprehensive genotyping platforms.[2] Additionally, power limitations can arise from moderate sample sizes or the analytical approaches employed; for instance, family-based association tests may have reduced power compared to total association tests because they primarily utilize information from individuals with heterozygous parents. [3] Performing analyses only in sex-pooled cohorts, rather than sex-specific investigations, could also obscure important associations that manifest differently between males and females. [4]
Furthermore, a significant concern in genome-wide association studies is the potential for false positive findings, especially when results have not been independently replicated in other cohorts. [5] Many initial p-values, particularly before stringent adjustment for multiple comparisons, may not represent true genetic associations. [3]Analytic choices, such as focusing exclusively on multivariable models, might also lead to overlooking important bivariate associations between single nucleotide polymorphisms and the traits of interest.[5] While imputation analyses can enhance coverage, their reliability depends on the quality of reference panels and stringent thresholds, such as considering only SNPs with an R-squared of 0.3 or higher [6]
Phenotype Measurement and Specificity
Section titled “Phenotype Measurement and Specificity”The accurate and precise measurement of phenotypes is critical for robust genetic association studies. However, practical constraints sometimes necessitate the use of proxy measures, which can introduce limitations. For example, using TSH as a sole indicator of thyroid function without measures of free thyroxine or a comprehensive assessment of thyroid disease might not fully capture the underlying physiological state.[5]Similarly, while markers like cystatin C are valuable for kidney function, their interpretation can be complicated by potential reflections of other conditions, such as cardiovascular disease risk, beyond their direct relation to kidney function.[5] Moreover, the reliance on existing transformation equations for traits like GFR can be problematic if these equations were developed in small, highly selected samples or using different analytical methods than those employed in a large, population-based cohort, thus limiting their appropriateness and potentially biasing results. [5]
Generalizability Across Diverse Populations
Section titled “Generalizability Across Diverse Populations”The generalizability of findings from genetic studies is often limited by the demographic characteristics of the studied cohorts. Many studies are conducted in populations that are not ethnically diverse or nationally representative, such as cohorts predominantly of White European ancestry. [5]This lack of diversity means that the applicability of identified genetic associations to other ethnic groups or broader populations remains uncertain. Genetic architecture can vary significantly across populations due to differences in allele frequencies, linkage disequilibrium patterns, and environmental exposures, implying that associations found in one group may not hold true or have the same effect size in another. Consequently, findings related to a sodium independent sulfate anion transporter in specific cohorts may not be directly translatable to individuals of different ancestral backgrounds without further validation in diverse populations.
The Need for Replication and Further Exploration
Section titled “The Need for Replication and Further Exploration”A fundamental limitation of initial genetic association findings is their provisional nature until confirmed through independent replication in other cohorts. [5] The absence of external replication makes it difficult to ascertain whether observed associations are true positive genetic signals or chance findings. Differences in study design, power, and genetic coverage across studies can influence the ability to replicate previously reported associations, even for the same trait. [7] Furthermore, current genome-wide association approaches, especially those utilizing less dense SNP arrays, may only capture a subset of all genetic variations, potentially missing genes or causal variants due to incomplete coverage. [2]This suggests that comprehensive understanding of a trait like a sodium independent sulfate anion transporter necessitates ongoing research with more advanced technologies and deeper functional studies to bridge remaining knowledge gaps and fully elucidate the genetic landscape.
Variants
Section titled “Variants”Variants within genes such as CFH, VTN, SARM1, and LINC01322 play diverse roles in human physiology, influencing processes from immune regulation to neuronal health and gene expression. The rs34813609 variant is located within the CFH gene, which encodes Complement Factor H, a critical soluble regulator of the alternative complement pathway, a branch of the innate immune system. This protein helps protect host cells from complement-mediated damage by inhibiting C3 convertase activity and acting as a cofacto Dysregulation of CFH due to variants like rs34813609 can lead to chronic inflammation or immune-mediated tissue damage, which can indirectly impact cellular metabolic demands and membrane integrity, potentially influencing the activity or regulation of sodium independent sulfa
The rs704 variant is notable for its association with two distinct genes: VTN and SARM1. The VTNgene encodes vitronectin, a multifunctional glycoprotein found in plasma and the extracellular matrix, involved in cell adhesion, migration, and regulation of the comp Simultaneously,rs704 is also associated with SARM1 (Sterile Alpha and Toll/Interleukin-1 Receptor Motif Containing 1), a gene centrally involved in programmed axon degeneration, a critical process for nervous system development and respon Variants like rs704 affecting either VTN’s extracellular matrix and immune functions or SARM1’s neuronal integrity role could broadly influence cellular health and tissue homeostasis, potentially affecting the need for sulfate in metabolic pathways, detoxification, or maintaining membrane integrity in response to cellular stress or injury, which in turn influences sodium independent sulfate anion transporter activity.
Lastly, the rs62295996 variant is located within LINC01322, a long intergenic non-protein coding RNA (lncRNA). LncRNAs are an extensive class of RNA molecules that do not code for proteins but play crucial regulatory roles in gene expression, chromati A variant such as rs62295996 in LINC01322could alter the lncRNA’s structure, stability, or its ability to interact with target genes, thereby affecting the expression of downstream genes. This regulatory influence could extend to genes involved in cellular metabolism, membrane transport, or specific pathways that impact the function or regulation of sodium independent sulfate anion transporters, which The indirect regulatory effects of lncRNAs mean that variants within them can have widespread consequences for cellular physiology.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs34813609 | CFH | insulin growth factor-like family member 3 measurement vitronectin measurement rRNA methyltransferase 3, mitochondrial measurement secreted frizzled-related protein 2 measurement Secreted frizzled-related protein 3 measurement |
| rs704 | VTN, SARM1 | blood protein amount heel bone mineral density tumor necrosis factor receptor superfamily member 11B amount low density lipoprotein cholesterol measurement protein measurement |
| rs62295996 | LINC01322 | blood protein amount coiled-coil domain-containing protein 126 measurement palmitoyl-protein thioesterase 1 measurement neurexin-1 measurement pregnancy-specific beta-1-glycoprotein 5 measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Defining Anion Transporters and Related Nomenclature
Section titled “Defining Anion Transporters and Related Nomenclature”Anion transporters are integral membrane proteins facilitating the movement of negatively charged molecules across biological membranes. One notable example discussed in research is SLC2A9, identified as a urate transporter, which also holds characteristics of a putative glucose transporter.[8]Its functional definition centers on its role in regulating the concentration of urate, an organic anion, within the body, impacting both serum levels and urinary excretion.[8]Key terminology in this field includes “urate transporter,” which explicitly describes proteins mediating urate movement, and “organic anion transporters” (OATs), a broader class of proteins known to be critically involved in renal handling of various anions. [9]
Classification and Physiological Significance of Urate Transporters
Section titled “Classification and Physiological Significance of Urate Transporters”Transporters involved in urate homeostasis, such asSLC2A9, can be classified based on their substrate specificity and predominant tissue expression. SLC2A9 is expressed strongly in the kidney and liver, and also found at low levels in chondrocytes, highlighting its involvement in metabolic pathways. [9]Its physiological significance lies in its influence on serum urate concentration and excretion, which directly correlates with conditions such as hyperuricemia and gout.[8] Beyond SLC2A9, the kidney’s pivotal role in urate handling involves a complex interplay of other classified transporters, including multiple organic anion transporters (OATs1-4) and urate anion transporters (URAT1, UAT), forming a nosological system for understanding urate metabolism.[9]
Measurement and Genetic Association of Urate Levels
Section titled “Measurement and Genetic Association of Urate Levels”The operational definition of transporter function is often inferred through the measurement of affected metabolite levels and genetic associations. Serum urate concentration, typically measured from blood samples collected after an overnight fast, serves as a primary biomarker for assessing the impact of urate transporters.[7]Diagnostic criteria for conditions like hyperuricemia commonly use a threshold, such as serum urate exceeding 0.4 mMol/l.[9] Research criteria involve genome-wide association studies (GWAS) to identify common genetic variants, like those in SLC2A9, that significantly influence these serum urate levels, utilizing statistical approaches like linear regression models adjusted for factors such as age and sex.[8] These genetic insights provide a conceptual framework for understanding the heritability and polygenic nature of traits influenced by transporters. [10]
Biological Background: SLC2A9and Urate Homeostasis
Section titled “Biological Background: SLC2A9and Urate Homeostasis”Role of SLC2A9in Urate Homeostasis
Section titled “Role of SLC2A9in Urate Homeostasis”The protein SLC2A9, also recognized as GLUT9, is a critical component in the body’s management of urate, significantly influencing both its concentration in the serum and its excretion. As a member of the facilitated hexose transporter family (SLC2A), SLC2A9was initially noted for its capacity to transport sugars like glucose and fructose, but subsequent research has firmly established its primary function as a urate transporter.[8]This protein plays an essential role in mediating the movement of urate across cellular membranes, a fundamental process required for maintaining proper levels of this metabolite. Its activity directly impacts the delicate homeostatic balance of urate, influencing how much circulates in the bloodstream and how efficiently it is eliminated.
The SLC2A9 protein, typically composed of 540 amino acids, exhibits a varied distribution across different bodily tissues. While it is most prominently expressed in the kidney and liver, it is also found in other areas such as the placenta, chondrocytes, brain, lung, and leukocytes. [11] A distinct splice variant of SLC2A9, known as GLUT9ΔN, is a 512-amino acid protein specifically expressed in the kidney and placenta. This variant is notably localized to the apical membrane of human kidney proximal tubule epithelial cells, underscoring its pivotal role in the renal mechanisms that regulate uric acid.
Genetic Mechanisms of Urate Regulation viaSLC2A9
Section titled “Genetic Mechanisms of Urate Regulation viaSLC2A9”Genetic variations within the SLC2A9gene are strongly associated with individual differences in serum uric acid levels. Numerous single nucleotide polymorphisms (SNPs) have been identified, including those located within introns 4 and 6, and in the noncoding and promoter regions ofSLC2A9. [12] These genetic variants can modify the gene’s regulatory elements, thereby affecting its expression patterns and, consequently, the quantity and activity of the SLC2A9protein. The association between these genetic factors and uric acid concentrations often demonstrates pronounced sex-specific effects, indicating complex regulatory networks that govern urate metabolism.[12]
The SLC2A9 gene extends across approximately 195 kilobases and contains 12 exons, with alternative splicing being a known mechanism that influences the trafficking of the protein. [11] The presence of various isoforms, such as SLC2A9isoform 2, which has been significantly linked to urate concentrations, highlights the intricate nature ofSLC2A9 function. [12] Furthermore, specific non-synonymous coding SNPs, including Ala17Thr (rs6820230 ), Val253Ile (rs16890979 ), and Arg265His (rs3733591 ), are located within the gene and may directly impact the protein’s structure and function, thereby modulating its efficiency in urate transport.[11]
Renal Physiology and Uric Acid Transport
Section titled “Renal Physiology and Uric Acid Transport”The kidney plays a central and indispensable role in maintaining uric acid homeostasis, meticulously managing urate reabsorption and excretion to prevent either harmful accumulation or excessive loss. This complex physiological process relies on a diverse network of transporters, including various organic anion transporters (OATs1-4 and OATv1) and other urate anion transporters such asURAT1 and UAT, which collectively regulate the kidney’s handling of urate.[9]The coordinated actions of these transporters are crucial in determining the ultimate concentration of uric acid found in both blood and urine.
Within this sophisticated renal system, the GLUT9ΔN splice variant of SLC2A9 is particularly significant. Its specific expression and strategic location on the apical membrane of human kidney proximal tubule epithelial cells underscore its importance. [11]This precise positioning is critical because the proximal tubule represents the primary site for renal uric acid regulation, where the majority of urate reabsorption and secretion events take place. The specific function ofSLC2A9as a urate transporter within this vital segment of the nephron directly impacts the efficiency of urate excretion, establishing it as a key factor in the overall physiological control of uric acid levels.
Pathophysiological Implications of Dysregulated Urate
Section titled “Pathophysiological Implications of Dysregulated Urate”Dysregulation of serum uric acid levels, often influenced bySLC2A9function, carries significant pathophysiological consequences, most notably manifesting as gout. This painful inflammatory arthritis is characterized by the precipitation and deposition of uric acid crystals within joints, a direct outcome of elevated serum urate concentrations.[8] The identification of SLC2A9as a key urate transporter provides a molecular basis for understanding the genetic susceptibility to hyperuricemia and gout, highlighting the gene’s potential as a target for therapeutic interventions.
Beyond its role in gout, altered serum uric acid levels are linked to a broader spectrum of clinical conditions, including cardiovascular disease, hypertension, and various metabolic disorders.[9]Elevated urate has been implicated in mechanisms such as enhanced renin release from the kidney, which can lead to vasoconstriction and contribute to the development of hypertension.[9]Furthermore, while uric acid serves as an antioxidant defense in humans, chronically high concentrations can exacerbate systemic inflammation and oxidative stress, thereby playing a role in the progression of these widespread health issues.[13]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Molecular Transport and Substrate Specificity
Section titled “Molecular Transport and Substrate Specificity”The sodium-independent sulfate anion transporter, identified asSLC2A9 (also known as GLUT9), is fundamentally a member of the facilitative glucose transporter protein family.[8]This classification implies its primary role involves the passive transport of specific solutes across cell membranes down their concentration gradients, a process crucial for cellular energy metabolism. While initially recognized for its structural homology to glucose transporters, subsequent research has predominantly characterizedSLC2A9as a significant transporter of urate, influencing its concentrations in serum and its excretion.[8] Its expression profile, with strong presence in the kidney and liver and lower levels in chondrocytes, highlights its organ-specific roles in maintaining metabolic homeostasis. [9]
Beyond urate, the classification ofSLC2A9 within the GLUTfamily and the mention of fructose in associated MeSH terms suggest potential broader implications in carbohydrate metabolism.[8]However, its direct involvement in glucose or fructose transport pathways in a physiological context, beyond structural classification, is still being elucidated. The protein’s ability to transport diverse substrates, or its facilitative nature for urate, underscores a crucial metabolic control point, allowing cells to adjust their internal environment and contribute to systemic balances.
Regulation of Urate Metabolism and Excretion
Section titled “Regulation of Urate Metabolism and Excretion”SLC2A9plays a pivotal role in the metabolic pathways governing urate homeostasis, significantly impacting serum urate levels and renal urate excretion.[8]Although the exact mechanisms of its action within the kidney are still being explored, its strong expression in kidney tissue is consistent with a critical function in regulating the flux of urate between the blood and the urine.[9]The kidney meticulously handles urate through a complex interplay of various organic anion transporters (OATs) and urate anion transporters (URAT1), and SLC2A9contributes to this intricate regulatory network, working alongside these systems to maintain urate balance.[9]
The influence of SLC2A9on uric acid concentrations exhibits pronounced sex-specific effects, indicating an additional layer of metabolic regulation that may involve hormonal or other sex-linked physiological differences.[14]This differential regulation further emphasizes the complex control mechanisms governing urate metabolism, a process essential for preventing the accumulation of uric acid and its associated pathological consequences. Changes in the activity or expression ofSLC2A9can thus directly alter the metabolic flux of urate, impacting its systemic levels and excretion rates.
Genetic and Post-Translational Modulators
Section titled “Genetic and Post-Translational Modulators”The activity and localization of SLC2A9are subject to various regulatory mechanisms, including genetic variation and post-translational modifications. Single nucleotide polymorphisms (SNPs) within theSLC2A9gene are strongly associated with serum uric acid levels, highlighting a genetic regulatory component that influences individual differences in urate homeostasis.[10]These genetic variants can potentially affect gene expression, protein stability, or transporter efficiency, thereby modulating the overall capacity for urate transport.
Furthermore, SLC2A9 undergoes post-translational regulation, specifically through alternative splicing, which has been shown to alter the trafficking of the protein. [15] Different splice variants of SLC2A9 (GLUT9) are expressed in tissues like the adult liver and kidney, and notably, these variants are observed to be up-regulated in conditions such as diabetes in mouse models. [16] This demonstrates a dynamic regulatory mechanism where the cell can produce different isoforms with potentially altered transport characteristics or subcellular localizations in response to physiological or pathological states, offering a crucial point for fine-tuning its function.
Crosstalk with Metabolic and Cardiovascular Systems
Section titled “Crosstalk with Metabolic and Cardiovascular Systems”Dysregulation of SLC2A9-mediated urate transport mechanisms is implicated in a broader network of metabolic and cardiovascular diseases, signifying a critical systems-level integration of its function. Elevated serum urate levels, often influenced bySLC2A9variants, are frequently correlated with conditions such as hypertension, coronary artery disease, and other metabolic disorders.[9]This suggests significant pathway crosstalk where altered urate metabolism can contribute to or exacerbate these complex multifactorial diseases.
Mechanisms proposed to explain the correlation between high urate and hypertension include enhanced renin release from the kidney, which subsequently leads to vasoconstriction.[9] This illustrates an emergent property where changes in a single transporter’s function can ripple through hormonal and vascular regulatory pathways, affecting systemic blood pressure. Consequently, SLC2A9dysregulation represents a disease-relevant mechanism, particularly in the pathogenesis of gout, a condition directly linked to elevated serum urate.[8]Understanding these network interactions and hierarchical regulation provides potential therapeutic targets for managing not only gout but also associated cardiometabolic comorbidities.
Clinical Relevance
Section titled “Clinical Relevance”Genetic Determinants of Urate Homeostasis and Gout
Section titled “Genetic Determinants of Urate Homeostasis and Gout”Genetic variants within the SLC2A9 gene, also known as GLUT9, are recognized as significant determinants of serum uric acid (UA) concentrations and influence the risk of developing gout. Research across multiple cohorts has consistently demonstrated strong associations between common genetic variations inSLC2A9and serum urate levels, as well as urate excretion ([8], [9], [10], [11], [12]). For instance, specific single nucleotide polymorphisms (SNPs) within introns 4 and 6 ofSLC2A9have been found to significantly correlate with uric acid concentrations, with observed effects ranging from -0.23 to -0.36 mg/dl per copy of the minor allele ([12]). This genetic influence underscores SLC2A9’s role as a key regulator in renal urate handling, potentially explaining a notable portion of the variance in serum urate levels within diverse populations ([17]).
The impact of SLC2A9variants extends directly to the prevalence and risk of gout. Studies have shown a linear increase in mean UA levels and a corresponding rise in gout prevalence with an increasing number of risk alleles inSLC2A9 and other associated loci ([17]). Individuals with six risk alleles, for example, exhibited a crude prevalence of gout between 8–18%, compared to 1–2% for those with no risk alleles ([17]). The odds ratio for hyperuricemia (defined as serum urate >0.4 mMol/l) for a common allele inSLC2A9has been reported as 1.89 (95% CI = 1.36–2.61), highlighting its substantial effect on elevated urate levels ([9]). Furthermore, a significant gene-by-sex interaction has been observed for certain SLC2A9 SNPs, such as rs16890979 and rs2231142 , where these variants explain a greater proportion of UA level variance in one sex compared to the other, indicating sex-specific clinical implications ([17]).
Prognostic Value in Cardiometabolic Health
Section titled “Prognostic Value in Cardiometabolic Health”Beyond its direct role in urate homeostasis and gout, the genetic influence ofSLC2A9on serum urate levels carries significant prognostic value due to the well-established associations between uric acid and various cardiometabolic disorders. Elevated serum uric acid is a recognized correlate of conditions such as essential hypertension, coronary artery disease, and broader metabolic dysfunctions ([9], [11], [18], [19]). Although the precise mechanisms are complex, proposed links include urate-induced enhanced renin release leading to vasoconstriction, which contributes to hypertension and cardiovascular pathology ([9]).
The identified genetic variants in SLC2A9that influence serum urate can therefore serve as indirect prognostic markers for the long-term progression and outcomes of these associated conditions. For example, a SNP strongly associated with serum urate has also been linked to an increased risk of coronary artery disease ([9]). By understanding an individual’s genetic predisposition to elevated urate throughSLC2A9variants, clinicians may gain insight into their susceptibility to related cardiovascular and metabolic complications, allowing for earlier intervention or more intensive monitoring. The replication of these associations across multiple independent cohorts, including GRAPHIC, TwinsUK, KORA, SHIP, and SAPHIR studies, reinforces the robustness ofSLC2A9 as a genetic indicator in cardiometabolic health ([9], [12]).
Personalized Approaches for Risk Stratification and Management
Section titled “Personalized Approaches for Risk Stratification and Management”The strong genetic associations of SLC2A9with serum urate levels and gout offer a foundation for developing personalized medicine strategies. Genetic testing for keySLC2A9variants could provide valuable diagnostic utility by identifying individuals at higher genetic risk for hyperuricemia and gout, even before clinical symptoms manifest ([17]). This risk assessment allows for targeted prevention strategies, such as lifestyle modifications or prophylactic interventions, tailored to an individual’s specific genetic profile. Given the variable impact ofSLC2A9 variants across sexes, personalized approaches could also account for these gene-by-sex interactions to refine risk predictions and management plans ([12], [17]).
Furthermore, insights from SLC2A9genetics can inform treatment selection and monitoring strategies for conditions involving uric acid. For patients already diagnosed with hyperuricemia or gout, understanding their genetic background related toSLC2A9might help predict their response to urate-lowering therapies or guide the choice of specific uricosuric agents. Ongoing monitoring of urate levels in genetically high-risk individuals could be intensified, allowing for timely adjustments to treatment to prevent complications like severe gout flares or associated cardiometabolic issues ([9]). Such an integrated approach, combining genetic risk stratification with traditional clinical markers, holds potential for more effective and individualized patient care.
References
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[13] Ames, Bruce N., et al. “Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.”Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 11, 1981, pp. 6858-62.
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