Digenic inheritance of severe insulin resistance in a human pedigree

Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.     

Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.     

Post-mating clutch piracy in an amphibian

Female multiple mating and alternative mating systems can decrease the opportunity for sexual selection. Sperm competition is often the outcome of females mating with multiple males and has been observed in many animals, and alternative reproductive systems are widespread among species with external fertilization and parental care. Multiple paternity without associated complex behaviour related to mating or parental care is also seen in simultaneously spawning amphibians and fishes that release gametes into water. Here we report 'clutch piracy' in a montane population of the common frog Rana temporaria, a reproductive behaviour previously unknown in vertebrates with external fertilization. Males of this species clasp the females and the pair deposits one spherical clutch of eggs. No parental care is provided. 'Pirate' males search for freshly laid clutches, clasp them as they would do a female and fertilize the eggs that were left unfertilized by the 'parental' male. This behaviour does not seem to be size-dependent, and some males mate with a female and perform clutch piracy in the same season. Piracy affected 84% of the clutches and in some cases increased the proportion of eggs fertilized, providing direct fitness benefits both for the pirate males and the females. Sexual selection--probably caused by a strong male-biased sex ratio--occurs in this population, as indicated by size-assortative mating; however, clutch piracy may reduce its impact. This provides a good model to explore how alternative mating strategies can affect the intensity of sexual selection.     

Mathematics,Philosophical and Semantic Considerations on Infinity (II): Dialectical Vision

Human language has the characteristic of being open and in some cases polysemic. The word “infinite” is used often in common speech and more frequently in literary language, but rarely with its precise meaning. In this way the concepts can be used in a vague way but an argument can still be structured so that the central idea is understood and is shared with to the partners. At the same time no precise definition is given to the concepts used and each partner makes his own reading of the text based on previous experience and cultural background. In a language dictionary the first meaning of “infinite” agrees with the etymology: what has no end. We apply the word infinite most often and incorrectly as a synonym for “very large” or something that we do not perceive its completion. In this context, the infinite mentioned in dictionaries refers to the idea or notion of the “immeasurably large” although this is open to what the individual’s means by “immeasurably great.” Based on this linguistic imprecision, the authors present a non Cantorian theory of the potential and actual infinite. For this we have introduced a new concept: the homogon that is the whole set that does not fall within the definition of sets established by Cantor.     

On Spatial and Temporal ex mensura Boundaries

In this paper we will propose an empirical analysis of spatial and temporal boundaries. Unlike other proposals, which deal mainly with the commonsense level of the subject, we will ground our explication on well-established scientific practice and language. In this way we show how to reconsider in an innovative way questions such as the distinction between the bona fide boundaries and the fiat boundaries, the thickness and the ownership of the boundaries. At the same time we propose a division between ex mensura boundaries and qui vulgo dicuntur boundaries. What is it, therefore, that divides the atmosphere from the water? [Leonardo da Vinci, Notebooks]      

Functional and structural determinants of reverse operation in the pH-dependent oligopeptide transporter PepT1

The functional and structural basis of reverse operation of PepT1 has been studied in Xenopus oocytes expressing the wild-type and mutated forms of this protein. Using brief pulses from a negative holding potential, wild-type and Arg282 mutants exhibit outward currents in the presence of Gly-Gln. The reversal potential of these currents is affected by both pH and substrate concentration, confirming coupled transport in the wild type and in the mutants as well. Long-lasting voltage and current-clamp experiments show that the outward currents are only temporary, and reflect accumulation and/or depletion effects near the membrane. The ability to operate in reverse mode was confirmed in all isoforms by intracellular injection of substrate. The role of Arg282 and Asp341 in the reverse transport was also investigated using charged substrates. Positive Lys-Gly (but not Gly-Lys) showed enhanced transport currents in the Arg282 mutants. In contrast, negative Gly-Asp and Asp-Gly elicited modest currents in all isoforms.     

The beet R locus encodes a new cytochrome P450 required for red betalain production

Anthocyanins are red and violet pigments that color flowers, fruits and epidermal tissues in virtually all flowering plants. A single order, Caryophyllales, contains families in which an unrelated family of pigments, the betalains, color tissues normally pigmented by anthocyanins. Here we show that CYP76AD1 encoding a novel cytochrome P450 is required to produce the red betacyanin pigments in beets. Gene silencing of CYP76AD1 results in loss of red pigment and production of only yellow betaxanthin pigment. Yellow betalain mutants are complemented by transgenic expression of CYP76AD1, and an insertion in CYP76AD1 maps to the R locus that is responsible for yellow versus red pigmentation. Finally, expression of CYP76AD1 in yeast verifies its position in the betalain biosynthetic pathway. Thus, this cytochrome P450 performs the biosynthetic step that provides the cyclo-DOPA moiety of all red betacyanins. This discovery will contribute to our ability to engineer this simple, nutritionally valuable pathway into heterologous species.     

Phoretic behaviour of Attacobius attarum (Roewer, 1935) (Araneae: Corinnidae: Corinninae) dispersion not associated with predation?

Attacobius attarum spiders exhibit a phoretic behaviour on the winged sexual of Atta leaf-cutting ants during their mating flight. However, it is unclear if this behaviour is for dispersion or to facilitate the predation of ants in the new colonies. A nest of Atta sexdens was monitored on the day of the mating flight, and the winged ants, as well as the spiders, were collected. The results obtained corroborate the hypothesis that phoretic behaviour is commonly used for dispersion of the spider A. attarum, predominantly females. Of these spiders, 64 individuals of A. attarium were collected, of which 62 were females (96.9%) and two were males (3.1%). Regarding the winged leaf-cutting ants sampled, 378 females and 361 males were collected, totaling 739 individuals. Of these, 64 individuals (8.7%) had a spider attached to its back for phoretic dispersal and none was observed on the queens after the nuptial flight. In our study, A. attarum females perform phoretic dispersal into the environment on winged leaf-cutting ants but do not settle in the new nests.     

The Effects of Disaggregation on Forecasting Nonstationary Time Series

This paper focuses on the effects of disaggregation on forecast accuracy for nonstationary time series using dynamic factor models. We compare the forecasts obtained directly from the aggregated series based on its univariate model with the aggregation of the forecasts obtained for each component of the aggregate. Within this framework (first obtain the forecasts for the component series and then aggregate the forecasts), we try two different approaches: (i) generate forecasts from the multivariate dynamic factor model and (ii) generate the forecasts from univariate models for each component of the aggregate. In this regard, we provide analytical conditions for the equality of forecasts. The results are applied to quarterly gross domestic product (GDP) data of several European countries of the euro area and to their aggregated GDP. This will be compared to the prediction obtained directly from modeling and forecasting the aggregate GDP of these European countries. In particular, we would like to check whether long‐run relationships between the levels of the components are useful for improving the forecasting accuracy of the aggregate growth rate. We will make forecasts at the country level and then pool them to obtain the forecast of the aggregate. The empirical analysis suggests that forecasts built by aggregating the country‐specific models are more accurate than forecasts constructed using the aggregated data. Copyright © 2014 John Wiley & Sons, Ltd.