Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Some Common Iowa Fishes, May 1936

This booklet contains information on the fish industry in Iowa and how to manage and improve it. It also shows drawings of the anatomy of a fish and various breeds that are found in Iowa. It concludes with a list of native fishes known from Iowa.

Common human melanoma-associated antigen(s) detected by monoclonal antibodies.

Hybridoma cells have been derived from a fusion between mouse myeloma cells (P3-NSI/1Ag4) and spleen cells from a mouse immunized with membrane-enriched fractions from the human melanoma cell line Me-43. Of the 26 hybrids obtained, seven secreted antibodies which reacted with the melanoma cell line used for immunoassay. The specificity of the antibodies produced by the seven positive hybrids was further investigated on 16 melanoma cell lines, 15 other tumors, and 14 lymphoblastoid cell lines. The antibodies from four positive hybrids showed a broad reactivity, whereas those from three hybrids reacted exclusively with melanoma cells. The antibodies from two of these three hybrids, alpha-Mel/5 and alpha-Mel/14, seem to be directed against common melanoma antigen(s) since they reacted with all (with one exception) of the 16 melanoma cell lines tested only with five of the 16 melanoma lines. Reciprocal binding inhibition tests using [3H]leeucine-labeled antibodies showed that alpha-Mel/5 and alpha-Mel/14 antibodies were directed against different antigenic determinants.

Field Evaluation of Class A Subbase Using Fly Ash, MLR-87-3, 1988

This project consisted of slipforming a 4-inch thick econocrete subbase on a 6-mile section of US 63. The project location extends south from one mile south of Denver, Iowa to Black Hawk County Road C-66 and consisted of the reconstruction and new construction of a divided four-lane facility. The econocrete was placed 27.3 feet wide in a single pass. Fly ash was used in this field study to replace 30, 45 and 60 percent of the portland cement in three portland cement econocrete base paving mixes. The three mixes contained 300, 350 and 400 pounds of cementitious material per cubic yard. Two Class "C" ashes from Iowa approved sources were used. The ash was substituted on the basis of one pound of ash for each pound of cement removed. The work was done October 6-29, 1987 and May 25-June 9, 1988. The twelve subbase mixes were placed in sections 2500 to 3000 feet in length on both the north and southbound roadways. Compressive strengths of all mixes were determined at 3 and 28 days of age. Flexural strengths of all mixes were determined at 7 and 14 days. In all cases strengths were adequate. The freeze/thaw durability of the econocrete mixes used was reduced by increased fly ash levels but remained above acceptable limits. The test results demonstrate the feasibility of producing econocrete with satisfactory properties even using fly ash at substitution rates up to 45 percent.

Development of a Rational Characterization Method for Iowa Fly Ash, HR-286, 1988

This research project was conducted in an attempt to determine the cause of paste strength variability in Iowa fly ashes and to develop test methods to more adequately reflect fly ash physical and chemical characteristics. An extensive three year sampling and testing program was developed and initiated which incorporated fly ash from several Iowa power plants. Power plant design and operating data were collected. The variability was directly linked to power plant maintenance schedules and to sodium carbonate coal pretreatment. Fly ash physical and chemical properties can change drastically immediately before and after a maintenance outage. The concentrations of sulfate bearing minerals in the fly ash increases sharply during shutdown. Chemical, mineralogical, and physical testing indicated that the sodium, sulfate bearing minerals, lime and tricalcium aluminate contents of the fly ashes play important roles in the development of hydration reaction products in fly ash pastes. The weak pastes always contained ettringite as the major reaction product. The strong pastes contained straetlingite and monosulfoaluminate as the major reaction products along with minor amounts of ettringite. Recommendations for testing procedure changes and suggested interim test methods are presented.

Characterization of Fly Ash for Use in Concrete, HR-225, 1983

Recent construction of new generation power plants burning western coal within Iowa has resulted in fly Ash production on the order of 760,000 tons annually. Although fly ash has long been accepted as a valuable replacement for portland cement in concrete, most experience has been with fly ash generated from eastern bituminous coals. A few years ago, fly ash in Iowa was not a significant factor because production was small and economics dictated disposal as the better alternative than construction use. Today, the economic climate, coupled with abundance of the material, makes constructive use in concrete feasible. The problem is, however, fly ash produced from new power plants is different than that for which information was available. It seems fly ash types have outgrown existing standards. The objective of this study was to develop fundamental information about fly ashes available to construction in Iowa such that its advantages and limitations as replacement to portland cement can be defined. Evaluative techniques used in this work involve sophisticated laboratory equipment, not readily available to potential fly ash users, so a second goal was preliminary development of rapid diagnostic tests founded on fundamental information. Lastly, Iowa Department of Transportation research indicated an interesting interdependency among coarse aggregate type, fly ash and concrete's resistance to freeze-thaw action. Thus a third charge of this research project was to verify and determine the cause for the phenomena. One objective of this project was to determine properties of Iowa fly ashes and evaluate their relevance to use of the material as an admixture of PCC. This phase of the research involved two approaches. The first involved the development of a rapid method for determining quantitative elemental composition while the second was aimed at both qualitative and quantitative determination of compounds. X-ray fluorescence techniques were adapted for rapid determination of elemental composition of fly ash. The analysis was performed using a Siemens SR-200 sequential x-ray spectrometer controlled by a PDP-11-03 microcomputer. The spectrometer was equipped with a ten sample specimen chamber and four interchangeable analyzing crystals. Unfiltered excitation radiation was generated using a chromium tube at 50 KV and 48 ma. Programs for the spectrometer were developed by the Siemens Corporation.

Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

Evolutionary and ecological significance of non-shivering thermogenesis in the common vole

La production endogène à long terme de chaleur, même au repos, est une adaptation que l'on retrouve chez les animaux à sang chaud (les oiseaux et les mammifères). Cette production de chaleur a comme but le maintien d'une température constante du corps indépendamment de la température extérieure. A cette fin, les mammifères ont développé une forme de tissu spécialisé nommé tissu adipeux brun (BAT). Ce tissu est responsable de la conversion de nourriture en chaleur, procédé appelé thermogenèse sans frisson (NST = non-shivering thermogenesis). Durant ce procédé la uncoupling protein 1 (UCP1) convertit, au sein des mitochondries, la nourriture en chaleur au lieu de produire de l'ATP, molécule utilisée comme énergie cellulaire. On suppose que cette inefficacité de la conversion de la nourriture en ATP dans le BAT influence l'homéostasie de l'énergie, l'allocation des ressources ainsi que la régulation de processus gourmant en énergie comme la croissance et la reproduction. Afin de maintenir une température du corps constante, les mammifères doivent ajuster leur NST en fonction de la température ambiante. La NST devrait être donc plus importante que la croissance et la reproduction durant l'hiver que lors l'été/à haute altitude qu'à basse altitude. En effet, plusieurs études ont déjà démontré la dépendance de la NST aux divers paramètres environnementaux. Par contre, l'héritabilité de la NST ainsi que sa relation avec d'autres traits de caractère, ne sont que très peu connus, ceci malgré l'importance d'une telle information afin de pouvoir comprendre son potentiel évolutif. L'étude de l'importance évolutive et écologique sur la NST chez les campagnols des champs (Microtus arvalis) fut donc le but cette thèse de doctorat. Grâce aux informations collectées sur 4 générations de campagnols (chapitre 1), une dépendance saisonnière et journalière de la NST a été démontrée: elle augmente lors des périodes froides et diminue lors de la lactation. On a démontré que bien qu'étant plastique, la variation de la NST a une composante génétique significative. Elle est corrélée avec le taux d'activité métabolique au repos indiquant des contraintes intrinsèques. A l'aide d'une expérience de jardin commune, on a pu démontrer dans le chapitre 2 que les campagnols habitant en altitude ont une capacité génétique de thermogenèse sans frisson plus haute que celles de basse altitude. Ils produisent des portées plus petites et leur descendance grandit moins vite, surtout à partir du 10ème jour ce qui coïncide avec le début de la production de chaleur endogène. En choisissant artificiellement des campagnols avec une NST faible ou grande, on a pu démontrer une relation entre la NST et la développement de la masse corporelle. Les campagnols avec une haute NST grandissent plus lentement et sont plus légères à l'âge adulte que celles ayant une basse NST. A l'aide d'un croisement interligne entre les campagnols sélectionnés (avec basse et haute NST), on a pu montrer dans le chapitre 3 des effets « parent-of-origin >> du développement massique de la descendance, indiquant une empreinte génétique parentale. Cela veut dire que l'expression d'un allele dépend de l'origine parentale. De plus, des effets « parent-of-origin » des taux de base de norépinephrine et d'irisine ont pu être trouvés. Ces hormones sont connues pour influencer non seulement la TSF mais aussi d'autres caractéristiques. Ces influences ouvrent la voie à de nouvelles études sur la relation entre la TSF et l'histoire de vie. Dans le chapitre 4 on a démontré des effets à long terme de l'allocation des ressources en manipulant la taille des portées qui ont abouti à des différences dans l'investissement dans la reproduction et de la croissance de la descendance à la fois dans le cas de la reproduction manipulé et aussi dans le non - manipulée entre les femelles avec portées agrandies et réduites. Ensemble, ces résultats mettent en évidence le rôle central de la NST dans l'allocation des ressources sur la base d'un compromis entre le maintien et la croissance et ainsi transforme l'histoire de vie des mammifères. Ces études montrent comment les mammifères peuvent répondre rapidement à court et à long terme (c'est-à-dire par des réponses génétiques ou plastiques) à un changement rapide du climat. On montre aussi qu'il y a probablement une corrélation entre l'histoire de vie et des changements du comportement. Finalement mes résultats ont montré un lien étroit entre la NST et la croissance et les dimensions du corps. Ces résultats indiquent que le tissu adipeux brun et la NST pourraient être une cible thérapeutique intéressante pour traiter l'obésité.

Ammonium Phosphate/Fly Ash Road Base Construction, HR-294, 1993

The objective of this research project was to evaluate the construction and service performance of ammonium phosphate/fly ash (APFA) treated base courses of crushed fines and/or unprocessed sand. Specific test results related to construction of the test sections were included in the 1987 construction report by Iowa State University. The performance of the experimental sections is dealt with in this final report. This 1986 project demonstrated that in all cases the control sections utilizing a Type B base experienced dramatically less cracking in the surface than the APFA treated base sections. The cost per mix and subsequent surface maintenance costs for the APFA base sections, especially those having a substantial amount of limestone, were higher than the Type B base control sections. This type of construction may prove to be economical only when petroleum product costs escalate.

Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.

Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.

Fly Ash Concrete Compressive Strength and Freeze-Thaw Durability, MLR-81-06, 1981

The current study investigated the effect of fly ash class, source and amount on the compressive strength and freeze-thaw durability of fly ash concrete. Concrete aggregates of varying quality were also included as test variables. The current results and those obtained from previous laboratory and field work indicate that compressive strength can·be affected by fly ash class, source and amount while aggregate quality is shown to have no effect on strength. Freeze-thaw durability of fly ash concrete is strongly affected by aggregate quality and to a lesser degree by fly ash class, amount and source.

Some common indexes of group diversity: upper boundaries

Workgroup diversity can be conceptualized as variety, separation, or disparity. Thus, the proper operationalization of diversity depends on how a diversity dimension has been defined. Analytically, the minimal diversity must be obtained when there are no differences on an attribute among the members of a group, however maximal diversity has a different shape for each conceptualization of diversity. Previous work on diversity indexes indicated maximum values for variety (e.g., Blau"s index and Teachman"s index), separation (e.g., standard deviation and mean Euclidean distance), and disparity (e.g., coefficient of variation and the Gini coefficient of concentration), although these maximum values are not valid for all group characteristics (i.e., group size and group size parity) and attribute scales (i.e., number of categories). We demonstrate analytically appropriate upper boundaries for conditional diversity determined by some specific group characteristics, avoiding the bias related to absolute diversity. This will allow applied researchers to make better interpretations regarding the relationship between group diversity and group outcomes.