Papers of the Year
- Genome-Wide Association Study (GWAS) Identifies Multiple Loci Associated with Lung Function
- Genomic-Based Model Used to Predict Chemical Hepatocarcinogenicity
- Variations in Human Gut Microbiome Linked to Obesity
- Sun Exposure May Trigger Certain Autoimmune Diseases in Women
- Hexavalent Chromium in Drinking Water Causes Cancer in Rodents
- Clean Air Extends Life Expectancy
- Mapping RNA Polymerase II Stalling to Study Gene Regulation
- Skin Penetration Risk for Cadmium Selenide Nanomaterials Examined
- Surfactant Decreases Quenching in Brightly Fluorescent Single-Walled Nanotubes
- SIRT1 Identified as a Key Regulator of Hepatic Lipid Metabolism
- Genome-Wide Association Study Identifies Asthma Gene
- Calcium Signaling During Mitosis
- Genome-Wide Association Study Identifies Genes Increasing Heart Attack Risk
- DNA Scrunching During Gap Repair Synthesis
- Alzheimer's Disease Linked to Mitochondrial Damage
- Link Between Serum Cholesterol and Asthma
- Arsenic Compromises Immune Response
- Initiation of Repair of Random DNA Double-Strand Breaks Requires RAD50
- Carbon Nanotubes Can Affect the Lung's Lining
- Hippocampal Synaptic Plasticity Can Be Modified by Differential Calcium Handling
- Electronic "Nose" Smells Toxins
- Female Mice Neonatally Treated with Genistein Exhibit Reproductive Abnormalities
- Gene Variant Linked to Bladder Cancer
- Methoxyacetic Acid Disrupts Endogenous Estrogen Signaling
Of the more than 2,700 papers published by NIEHS-supported researchers in 2009, 24 publications were chosen as Papers of the Year.
Genome-Wide Association Study (GWAS) Identifies Multiple Loci Associated with Lung Function
In GWAS studies, investigators search for specific locations in the genome sequence where variations can be associated with different observable traits such as diseases. NIEHS researchers directed a GWAS study to help understand the genetic basis of human lung development, asthma, and chronic obstructive pulmonary disease (COPD).
The study combined data from more than 20,000 participants from multiple studies and looked at two clinically important lung-function measures –– forced expiratory volume and its ratio to forced vital capacity, an indication of airflow obstruction.
The analysis identified nine genetic loci associated with pulmonary function. Identifying these loci allow scientists to focus on these genes and determine how their interaction with environmental factors might cause disease.
Citation: Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. 2010. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet 42(1):45-52. [Abstract] [Newsletter Article] [News Release]
Genomic-Based Model Used to Predict Chemical Hepatocarcinogenicity
Of the estimated 30,000 chemicals in widespread commercial use in the U.S. and Canada, only a small fraction have been tested for carcinogenicity. The test for each chemical requires an expensive two-year bioassay followed by a scientific panel evaluation of its carcinogenic risk for humans.
NTP scientists developed a pattern recognition model that can identify hepatocarcinogens, based on the gene expression pattern of exposed animals, as an approach that allows prioritizing chemicals for testing. Using previously studied alkenylbenzenes, the model was able to correctly predict which were carcinogenic and the dose level that would cause carcinogenicity. The results showed that chemical exposure duration is a critical variable for the test.
Citation: Auerbach SS, Shah RR, Mav D, Smith CS, Walker NJ, Vallant MK, et al. 2009. Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning. Toxicol Appl Pharmacol Doi:10.1016/j.taap.2009.11.021. [Epub ahead of print] [Abstract]
Variations in Human Gut Microbiome Linked to Obesity
The human gut microbiome, which helps in digesting food, is made up of the microbial community, their genes, and their gut interactions. A study of the gut microbiome of lean and obese adult female twins and their mothers revealed that obesity was associated with lower numbers and different phyla of bacteria, and increases in bacterial genes that extract calories from food and process nutrients.
The results showed that the microbial community makeup varied between individuals, but that family members had very similar communities compared to unrelated individuals. The microbial genes present were sufficiently shared to identify a core microbiome of genes amongst the subjects.
Supported by NIEHS grant P50ES012742, John Stegeman, Ph.D., Woods Hole Oceanographic Institute.
Sun Exposure May Trigger Certain Autoimmune Diseases in Women
Dermatomyositis is an autoimmune muscle disease that weakens the muscles and causes distinctive rashes. NIEHS researchers collaborated with myositis centers across the country to determine if ultraviolet (UV) radiation from sunlight was associated with the development of dermatomyositis.
They found an association between UV radiation intensity and the proportion of patients with dermatomyositis and with the proportion of patients expressing myositis antibodies, anti-Mi-2 autoantibodies. The data suggest that sex influences the effects of UV radiation on autoimmune disorders because the associations were only found in women.
Citation: Love LA, Weinberg CR, McConnaughey DR, Oddis CV, Medsger TA Jr, Reveille JD, et al. 2009. Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women. Arthritis Rheum60(8):2499-2504. [Abstract] [Synopsis] [News Release]
Hexavalent Chromium in Drinking Water Causes Cancer in Rodents
Detectable levels of hexavalent chromium (Cr(VI)), an industrial chemical, has been reported in approximately 30 percent of the drinking water sources monitored in California. Cr(VI) is known to be carcinogenic to humans after inhalation exposure, but the effects from chronic oral exposure to Cr(VI) is unknown.
NTP scientists characterized the chronic oral toxicity and carcinogenicity of Cr(VI) in rats and mice, with a two-year drinking water study of sodium dichromate dihydrate (SDD). SDD is widely used in industry to produce chromium compounds. The exposed animals developed abnormal growths in the oral cavity and small intestine, providing clear evidence of carcinogenicity.
Citation: Stout MD, Herbert RA, Kissling GE, Collins BJ, Travlos GS, Witt KL, et al. 2009. Hexavalent chromium is carcinogenic to F344/N rats and B6C3F1 mice after chronic oral exposure. Environ Health Perspect 117(5):716-722. [Article] [NTP Fact Sheet]
Clean Air Extends Life Expectancy
Particulate matter in the air, such as from combustion by-products, can be inhaled into the lungs and cause heart and lung disease and, potentially, increased mortality. Researchers examined the association of exposure to 2.5 micrometer or less sized particulate matter (PM 2.5) pollution and life expectancy, in 51 metropolitan areas throughout the U.S. between 1980 and 2000.
They found that a decrease in 10 micrograms per cubic meter in the concentration of fine-particulate matter was associated with an estimated increase in mean life expectancy of 0.61 years. The scientists concluded that reducing ambient fine-particulate air pollution contributed to significant and measurable increases in life expectancy in the U.S.
Supported by NIEHS grant P30ES000002, Douglas Dockery, Sc.D., Harvard School of Public Health.
Mapping RNA Polymerase II Stalling to Study Gene Regulation
Contrary to the common belief that the recruitment of RNA polymerase II (Pol II) to a promoter is sufficient for gene activation and transcript elongation, a recent study has shown that promoter-proximal stalling, whereby Pol II accumulates at promoters and stalls, is widespread. Scientists from NIEHS and Virginia Commonwealth University developed a method to detect short RNAs derived from stalled Pol II in Drosophila cells and mapped them across the genome to determine where stalling occurred.
The research team showed that the sequence composition of initially transcribed regions is important in polymerase stalling. The results indicate that promoter-proximal stalling, which occurs in over one-third of all genes, provides a way of controlling transcription output thereby regulating gene expression.
Citation: Nechaev S, Fargo DC, dos Santos G, Liu L, Gao Y, Adelman K. 2010. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327(5963):335-338 [epub ahead of press] doi. 10.1126/science.1181421. [Abstract] [Synopsis]
Skin Penetration Risk for Cadmium Selenide Nanomaterials Examined
Nanoscale materials, which are reported to be in many cosmetics, sunscreens, and other consumer products, can potentially cross the skin and enter the body –– possibly causing harm.
To evaluate the risk of transdermal absorption, National Toxicology Program (NTP) scientists evaluated the penetration of polyethylene glycol-coated cadmium selenide core quantum dots (QD) into mouse skin, by monitoring internal sentinel organs –– liver and regional draining lymph nodes. The QD nanoscale material was applied to mouse skin in a cream, similar to those used in skin lotions and sunscreens.
The study results showed no QD penetration occurred in mice with intact skin, but in mice with dermabraded skin, the QD levels in the sentinel organs were elevated.
Citation: Gopee NV, Roberts DW, Webb P, Cozart CR, Siitonen PH, Latendresse JR, et al. 2009. Quantitative determination of skin penetration of PEG-coated CdSe quantum dots in dermabraded but not intact SKH-1 hairless mouse skin. Toxicol Sci 111(1):37-48. [Abstract]
Surfactant Decreases Quenching in Brightly Fluorescent Single-Walled Nanotubes
NIEHS-supported chemists discovered a way to increase the light-emitting efficiency of single-walled carbon nanotubes (SWNTs) as high as 20 percent.
Photoluminescent properties –– whereby light is emitted after light units called photons are absorbed –– make SWNTs potentially useful for optoelectronics, medical imaging, and sensing. However, the emission of light, or luminescence, can be reduced or quenched when oxygen settles on, and then binds to, the SWNT surface.
The researchers used a surfactant chemical derived from vitamin B-12 to coat the nanotubes. This coating prevents oxygen from binding to the SWNTs and helps prevent SWNT aggregation that can also reduce luminescence.
Citation: Ju SY, Kopcha WP, Papadimitrakopoulos F. 2009. Brightly fluorescent single-walled carbon nanotubes via an oxygen-excluding surfactant organization. Science 323(5919):1319-1323. [Abstract] [Synopsis]
Supported by NIEHS grant R01ES013557, James Rusling, Ph.D., University of Connecticut.
SIRT1 Identified as a Key Regulator of Hepatic Lipid Metabolism
Sirtuin 1 (SIRT1) is an important regulator of energy homeostasis, in response to nutrient availability in many metabolic pathways and tissues. NIEHS scientists showed that in the liver, SIRT1 regulates lipid metabolism, particularly fatty acid metabolism, by positively regulating peroxisome proliferator-activated receptor alpha (PPARa).
PPARa is a nuclear receptor that functions as a lipid sensor and activates genes metabolizing fatty acids. Overexpression of SIRT1 stimulated PPARa signaling. Liver-specific SIRT1 knockout mice had impaired PPARa signaling and developed fatty liver, inflammation, and endoplasmic reticulum stress, after a high fat diet. Thus, SIRT1 may be a therapeutic target for prevention of obesity-associated metabolic diseases.
Citation: Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. 2009. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab9(4):327-338. [Abstract] [Synopsis] [Newsletter Article]
Genome-Wide Association Study Identifies Asthma Gene
Asthma is a complex chronic airway disease that affects more than 20 million Americans and 300 million people worldwide. A multicenter genome-wide association (GWA) analysis identified the phosphodiesterase 4D (PDE4D) gene as an asthma susceptibility gene.
Two PDE4D single nucleotide polymorphisms (SNPs) were significantly associated with asthma. PDE4D is involved in controlling airway smooth muscle contraction. Phosphodiesterase inhibitors are used to treat asthma. Studying the PDE4D SNPs can lead to a better understanding of how PDE4D is involved in asthma and how PDE4D inhibitors work.
Citation: Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, et al. 2009. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 84(5):581-593. [Abstract] [Synopsis]
Supported by NIEHS grants P01ES011627 and P30ES007048, Frank Gilliland, M.D., Ph.D., University of Southern California.
Calcium Signaling During Mitosis
Cells use calcium ion (Ca2+) levels as a component in some of their signaling networks that help coordinate and control cellular processes. NIEHS scientists showed that phosphorylation of stromal interaction molecule 1 (STIM1), a Ca2+ sensor protein, occurs specifically during mitosis and suppresses store-operated Ca2+ entry (SOCE).
With Ca2+ store depletion, STIM1 normally moves to spot-like structures in the ER near the plasma membrane, a critical step in activating SOCE. The study showed that, due to STIM1 phosphorylation, this movement did not occur in mitotic cells thereby potentially protecting these cells from harmful Ca2+ influx.
Citation: Smyth JT, Petranka JG, Boyles RR, DeHaven WI, Fukushima M, Johnson KL, et al. 2009. Phosphorylation of STIM1 underlies suppression of store-operated calcium entry during mitosis. Nat Cell Biol11(12):1465-1472. [Abstract] [Synopsis] [Newsletter Article]
Genome-Wide Association Study Identifies Genes Increasing Heart Attack Risk
Myocardial infarction (MI), or heart attack, is a leading cause of death and disability worldwide. MI is a heritable disease with inherited genes having a greater impact on early-onset MI –– heart attacks in men 50 or women 60 years old or younger.
The Myocardial Infarction Genetics Consortium (MIGC) conducted a genome-wide association study that identified nine single nucleotide polymorphisms (SNPs) associated with early-onset MI –– three of the SNPs are newly identified. The MIGC also tested copy number variants, but did not find any association between the number of specific gene copies in an individual's genes and risk of early-onset MI.
Citation: Myocardial Infarction Genetics Consortium. 2009. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 41(3):334-341. [Abstract] [Synopsis]
Supported by NIEHS grant P30ES007033, David Eaton, University of Washington.
DNA Scrunching During Gap Repair Synthesis
Normal metabolic activities and environmental exposures, such as UV light, can cause structural damage to DNA and mutations. Polymerase lambda (Pol l), a DNA repair enzyme, can fill in short gaps of 1–6 missing nucleotides (nt) in damaged DNA. DNA binding and gap filling are well characterized for 1 nt gaps, but the location of yet-to-be copied template nucleotides in longer gaps is unknown.
NIEHS scientists, collaborating with investigators at the University of North Carolina at Chapel Hill and Stony Brook University in New York, determined crystal structures showing that, when bound to a 2- nt gap, Pol l scrunches the template strand and binds the additional yet-to-be-copied template base in an extrahelical position within a binding pocket that comprises three conserved amino acids.
This study sheds light on the specific structural changes necessary during DNA repair and, ultimately, the protection against mutations due to environmental exposures.
Citation: Garcia-Diaz M, Bebenek K, Larrea AA, Havener JM, Perera L, Krahn JM, et al. 2009. Template strand scrunching during DNA gap repair synthesis by human polymerase lambda. Nat Struct Mol Biol 16(9):967-972. [Abstract] [Synopsis]
Alzheimer's Disease Linked to Mitochondrial Damage
Alzheimer's disease (AD) is a progressive and fatal brain disease, characterized by damage and death of neurons, that has no current cure. A new study on a mitochondrial protein, dynamin-related protein 1 (Drp1), suggests that Drp1 could be a new drug target to reduce or even prevent neurodegeneration in Alzheimer's patients.
The researchers found that Drp1 is S-nitrosylated by nitric oxide, whereby the oxygen of nitric oxide binds to a sulfur in Drp1 in response to oligomers of beta-amyloid — a protein considered a key mediator in AD — causing neuronal mitochondrial and synaptic damage like that seen in AD.
Citation: Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. 2009. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324(5923):102-105. [Abstract] [Synopsis]
Supported by NIEHS grant P01ES016738, Stuart Lipton, M.D., Ph.D., Burnham Institute for Medical Research.
Link Between Serum Cholesterol and Asthma
Cholesterol has complex effects on inflammation, but its effects on asthma, an inflammatory airway disease, is unknown. NIEHS scientists collaborated with investigators at SRA International, Inc. and Rho Federal Systems Division, Inc. to determine relationships between levels of three serum cholesterol measures and asthma or wheeze in a sample of 7005 participants that was representative of the U.S. population.
High-density lipoprotein cholesterol was not different in patients with or without current asthma. However, asthma was inversely related to serum total cholesterol and non-high-density lipoprotein cholesterol chiefly reflecting a relationship among Mexican Americans. These results may explain why Mexican Americans have the lowest prevalence of asthma in the country, despite increased asthma risk factors.
Citation: Fessler MB, Massing MW, Spruell B, Jaramillo R, Draper DW, Madenspacher JH, et al. 2009. Novel relationship of serum cholesterol with asthma and wheeze in the United States. J Allergy Clin Immunol 124(5):967-974. [Abstract] [Newsletter Article]
Arsenic Compromises Immune Response
As many as 25 million Americans and hundreds of millions of people worldwide are exposed to arsenic in their drinking water.
A new study demonstrated that a five-week exposure to a low dose of 100 parts per billion of arsenic in drinking water significantly compromised the immune response to respiratory influenza A (H1N1) in mice.
The researchers hypothesized that chronic arsenic exposure could contribute to increased lung disease risk in humans. They also suggested that in areas like Southeast Asia and Mexico that have very high levels of arsenic in drinking water, the impact of a pandemic strain of influenza could be enhanced.
Citation: Kozul CD, Ely KH, Enelow RI, Hamilton JW. 2009. Low dose arsenic compromises the immune response to influenza A infection in vivo. Environ Health Perspect 117(9):1441-1447. [Abstract]
Supported by NIEHS grant P42ES007373,Bruce Stanton, Ph.D., Dartmouth Medical School.
Initiation of Repair of Random DNA Double-Strand Breaks Requires RAD50
Little is known about how cells repair random DNA double-strand breaks (DSBs), such as those caused by gamma radiation, a therapy commonly used in cancer treatment. NIEHS researchers and an Indiana University-Purdue University Indianapolis collaborator found a way to track early events in repairing DSBs caused by gamma irradiation in yeast using pulsed field gel electrophoresis (PFGE).
The investigators demonstrated that the initial step in repair of random DSBs involved resection, the removal of one of the strands at a DSB end, and that this step depends on the MRX complex composed of the proteins Mre11, Rad50, and Xrs2. Yeast lacking Rad50 or Mre11 were slow in generating resected ends, a key step in DSB repair.
Citation: Westmoreland J, Ma W, Yan Y, Van Hulle K, Malkova A, Resnick MA. 2009. RAD50 is required for efficient initiation of resection and recombinational repair at random, gamma-Induced double-strand break ends. PLoS Genet5(9):e1000656. [Abstract] [Synopsis]
Carbon Nanotubes Can Affect the Lung's Lining
Carbon nanotubes (CNTs), present in many products, are similar to asbestos in that they are fiber-shaped. It is unknown if CNTs are comparable to asbestos in causing lung disease in humans, such as lung tissue scarring and mesothelioma, and cancer of the pleura.
Researchers found that multiwalled CNTs (MWCNTs) reach the subpleura, the lining of the lung, in mice exposed to one single six hour inhalation of 30 milligrams per cubic meter of MWCNTs, causing the accumulation of immune cells at the pleural surface within the first day and lung scarring after two weeks.
Asbestos exposure also results in subpleural scarring suggesting that individuals with occupational MWCNT inhalation exposure could be at risk for lung disease.
Citation: Ryman-Rasmussen JP, Cesta MF, Brody AR, Shipley-Phillips JK, Everitt JI,Tewksbury EW, et al. 2009. Inhaled carbon nanotubes reach the subpleural tissue in mice. Nat Nanotechnol 4(11):747-751. [Abstract] [Synopsis] [Newsletter Article]
Supported by NIEHS grant R21ES015801, James Bonner, Ph.D., North Carolina State University.
Hippocampal Synaptic Plasticity Can Be Modified by Differential Calcium Handling
Scientists at the NIEHS and Duke University examined neurons from different subareas –– CA1, CA2, and CA3 –– of the hippocampus, a brain area involved in memory formation, to understand the mechanisms underlying synaptic plasticity, as measured by long-term potentiation (LTP).
The scientists showed that CA2 neurons, which do not reliably display LTP, have lower postsynaptic calcium ion (Ca2+) concentrations due to Ca2+ buffering and higher rates of Ca2+ extrusion, when compared to CA1 and CA2. The results indicate that CA2 neurons have the cellular machinery required for plasticity, but the expression is modulated by Ca2+ handling. Other brain regions may have this same modulation.
Citation: Simons SB, Escobedo Y, Yasuda R, Dudek SM. 2009. Regional differences in hippocampal calcium handling provide a cellular mechanism for limiting plasticity. Proc Natl Acad Sci USA 106(33):14080-14084. [Abstract] [Synopsis]
Electronic "Nose" Smells Toxins
Scientists have developed a postage stamp-sized sensor that can rapidly detect and identify poisonous gases with an array of pigmented dots that displays a different color pattern, or fingerprint, specific to each gas.
The researchers tested their sensor with 19 diverse toxic industrial chemicals that can be dangerous to life or health, including ammonia, chlorine, and sulfur dioxide. The sensor was able to accurately identify each chemical, usually well below their permissible exposure limit concentrations, within seconds to two minutes.
Security, as well as occupational exposure monitoring, has an immediate need for the sensor's ability to rapidly identify and quantify a wide variety of toxic gases.
Supported by NIEHS grant U01ES016011, Kenneth Suslick, Ph.D., University of Illinois at Urbana-Champaign.
Female Mice Neonatally Treated with Genistein Exhibit Reproductive Abnormalities
The phytoestrogen genistein is a naturally occurring estrogenic chemical found in soy and soy-based infant formulas. Female mice treated neonatally with genistein have multioocyte follicles, lack regular estrous cyclicity, and are infertile even after superovulation.
NIEHS investigators studied oocyte developmental competence and timing of embryo loss in genistein-exposed mice, to determine the cause of their infertility. The scientists found that mice neonatally treated with genistein developed competent oocytes, but because genistein exposure produced an abnormal oviductal environment, the oocytes were unable to implant in the uterus, leading to reproductive failure.
Citation: Jefferson WN, Padilla-Banks E, Goulding EH, Lao SP, Newbold RR, Williams CJ. 2009. Neonatal exposure to genistein disrupts ability of female mouse reproductive tract to support preimplantation embryo development and implantation. Biol Reprod 80(3):425-431. [Abstract] [Synopsis]
Gene Variant Linked to Bladder Cancer
In the U.S., bladder cancer is the fourth most common cancer in men. In a genome-wide association study, scientists have discovered a new susceptibility gene for bladder cancer in the U.S. and European populations — a gene variant of the prostate stem cell antigen (PSCA) gene.
One nucleotide difference in the gene variant alters the starting point of transcription and results in the deletion of nine amino acids in the N-terminal localization sequence of the protein that directs the unprocessed protein to modification sites. The gene variation significantly reduces promoter activity, making protein synthesis less efficient. The PSCA variant is common in U.S. and European populations.
Citation: Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T, Matullo G, et al. 2009. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet 41(9):991-995. [Abstract] [Synopsis]
Supported by NIEHS grant P42ES007373, Bruce Stanton, Ph.D., Dartmouth Medical School.
Methoxyacetic Acid Disrupts Endogenous Estrogen Signaling
Exposure from both ethylene glycol monomethyl ether (EGME), an industrial solvent, and its primary metabolite, methoxyacetic acid (MAA), has been linked to reproductive toxicity in epidemiology studies. NIEHS scientists and a collaborator from the German Cancer Research Center evaluated the mechanistic effects of MAA on estrogen receptor (ER) expression and estrogen signaling.
MAA activated the cytomegalovirus promoter to stimulate exogenous ER expression in an in vitro system. In contrast, MAA decreased endogenous ERa expression and attenuated 17b-estradiol-stimulated endogenous gene expression in MCF-7 cells and mouse uterus. The results suggest that EGME and MAA toxic effects may be due, at least in part, to attenuation of endogenous ER-mediated signaling.
Citation: Henley D V, Mueller S, Korach KS. 2009. The short-chain fatty acid methoxyacetic acid disrupts endogenous estrogen receptor-a-mediated signaling. Environ Health Perspect 117(11):1702-1706. [Abstract] [Synopsis]