Simple-sugar meals target GLUT2 at enterocyte apical membranes to improve sugar absorption: a study in GLUT2-null mice.

The physiological significance of the presence of GLUT2 at the food-facing pole of intestinal cells is addressed by a study of fructose absorption in GLUT2-null and control mice submitted to different sugar diets. Confocal microscopy localization, protein and mRNA abundance, as well as tissue and membrane vesicle uptakes of fructose were assayed. GLUT2 was located in the basolateral membrane of mice fed a meal devoid of sugar or containing complex carbohydrates. In addition, the ingestion of a simple sugar meal promoted the massive recruitment of GLUT2 to the food-facing membrane. Fructose uptake in brush-border membrane vesicles from GLUT2-null mice was half that of wild-type mice and was similar to the cytochalasin B-insensitive component, i.e. GLUT5-mediated uptake. A 5 day consumption of sugar-rich diets increased fructose uptake fivefold in wild-type tissue rings when it only doubled in GLUT2-null tissue. GLUT5 was estimated to contribute to 100 % of total uptake in wild-type mice fed low-sugar diets, falling to 60 and 40 % with glucose and fructose diets respectively; the complement was ensured by GLUT2 activity. The results indicate that basal sugar uptake is mediated by the resident food-facing SGLT1 and GLUT5 transporters, whose mRNA abundances double in long-term dietary adaptation. We also observe that a large improvement of intestinal absorption is promoted by the transient recruitment of food-facing GLUT2, induced by the ingestion of a simple-sugar meal. Thus, GLUT2 and GLUT5 could exert complementary roles in adapting the absorption capacity of the intestine to occasional or repeated loads of dietary sugars.

Solvent vapours in incubators: a source of exposure among neonates?

Hygiene practices in neonatal units require the use of disinfecting solutions containing ethanol or isopropanol. Newly disinfected hands or soaked swabs introduced inside the incubators may emit vapours leading to alcohol exposures to the neonates. Alcohol emissions from hands and other occasional sources (e.g. soaked disinfecting swabs) lead to measurable levels of vapours inside incubators. Average isopropanol and ethanol concentrations ranging from 33.1 to 171.4 mg/m(3) (13.8 to 71.4 ppm) and from 23.5 to more than 146 mg/m3 (9.8 to > 6 ppm) respectively were measured inside occupied incubators (n = 11, measurement time about 230 min) in a neonatal unit of the Centre Hospitalier Universitaire Vaudois in Lausanne during regular activity. Exposure concentrations in a wide range of possible situations were then investigated by modeling using the one-box dispersion model. Theoretical modeling suggested typical isopropanol peaks and average concentrations ranging between 10(2) and 10(3) mg/m(3) (4.10(1) to 4.10(2)ppm), and 10(1) to 10(2) mg/m(3) (4 to 4.10(1) ppm), respectively. Based on our results we suggest several preventive measures to reduce the neonates' exposures to solvent vapours.

Ectodysplasin A (EDA)-EDA receptor signalling and its pharmacological modulation

L'ectodysplasine Al (EDA1 ou EDA), un ligand de la famille du TNF, et son récepteur EDAR favorisent le développement des poils, des dents et de plusieurs types de glandes. Chez l'humain, une déficience en EDA cause une dysplasie ectodermique liée à l'X, caractérisée par la genèse défectueuse des phanères. Les souris Tabby, déficientes en Eda, présentent des symptômes similaires. Nous démontrons que les souris Tabby sont en moyenne 7% plus légères que les contrôles au moment du sevrage. Ce phénotype ne dépend pas du génotype des petits, mais exclusivement de celui de la mère, suggérant que l'absence d'EDA perturbe la fonction mammaire. La glande mammaire se développe en plusieurs étapes, principalement à la puberté et pendant la grossesse. Nous avons généré des anticorps pour activer ou inhiber la signalisation d'EDAR. Les anticorps agonistes corrigent le développement de souris ou de chiens déficients en EDA, alors que les antagonistes provoquent une dysplasie ectodermique chez les souris saines. L'exposition répétée de souris Tabby aux anticorps agonistes après le sevrage accroît la taille et la fonction des glandes sébacées, démonstration pharmacologique qu'EDA contrôle l'homéostasie de la glande sébacée adulte. Ces outils seront utiles pour étudier la fonction d'EDA aux diverses étapes du développement de la glande mammaire. Fc-EDAl, un stimulateur d'EDAR, est en phase d'évaluation clinique. Nous avons montré que les structures dépendantes d'EDA qui se forment à différentes étapes du développement répondent à l'action du Fc-EDAl dans des fenêtres temporelles étroites ou larges. De plus, certaines structures peuvent être induites plusieurs jours après le début naturel de leur formation. Alors que la plupart des structures se forment suite à un seul jour d'activation d'EDAR, d'autre demandent un temps de stimulation plus long. La formation des dents est régulée par des signaux activateurs et inhibiteurs. Une forte stimulation d'EDAR spécifiquement appliquée aux deux premières molaires induit des signaux négatifs qui avortent la formation de la troisième molaire, alors qu'une forte stimulation donnée à la troisième molaire la rend hypertrophique tout en induisant parfois une quatrième molaire jamais observée chez les souris de type sauvage ou Tabby. EDA est donc un activateur important de la formation dentaire. Pris dans leur ensemble, ces résultats ont des implications pour la thérapie des dysplasies ectodermiques. - The TNF family ligand Ectodysplasin Al (EDA1 or EDA) and its receptor ED AR regulate embryonic development of hair, teeth and several types of glands. In humans, EDA mutations cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition characterized by defective development of skin appendages. £da-deficient (Tabby) mice suffer from similar defects. We observed that Tabby pups at weaning were on average 7% smaller than WT controls, a phenotype that was curiously not linked to the genotype of pups, but to that of mothers, suggesting decreased mammary gland function in the absence of EDA. Mammary glands develop in several steps, most of which are post-natal. We generated monoclonal antibodies to block or activate EDAR signaling. Agonist antibodies rescued developmental defects when administered timely in £cfo-deficient mice and dogs, whereas blocking antibodies induced ectodermal dysplasia in WT mice. Agonist antibodies administered after weaning in £da-deficient mice for several months markedly increased both size and function of sebaceous glands, providing the first demonstration that pharmacological activation of the EDAR pathway in adults can correct important aspects of the dry skin phenotype. This also highlights a role for EDA1 in the homeostasis of adult sebaceous glands. These tools will be useful to study the function of EDA 1 at different stages of mammary gland development. Another EDAR agonist, Fc-EDAl, is currently evaluated in clinical trials. We found that EDA 1-dependent structures forming at different time points during development can respond to Fc-EDAl during time response windows that are narrow or wide. Also, some structures can be triggered up to several days after their normal time of induction. While most structures could be rescued by a single day of EDAR signaling, others required longer exposure times to form. Tooth formation is regulated by activating and inhibitory signals that impact one on the other. When strong EDAR signals were specifically given to the first two molars, overwhelming inhibitory signals completely inhibited formation of the third molar. In contrast, strong signals specifically given to the third molar induced hypertrophy of the later with occasional appearance of a fourth molar never observed in WT or £da-deficient mice. This clearly positions EDA as an important activating signal in tooth formation. Taken together, these results have implications for the therapy of ectodermal dysplasias.

Modelling the evolution and spread of HIV immune escape mutants.

During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.

Mating frequency of ant queens with alternative dispersal strategies, as revealed by microsatellite analysis of sperm

In social Hymenoptera (ants, bees, and wasps), the number of males that mate with the same queen affects social and genetic organization of the colony. However, the selective forces leading to single mating in certain conditions and multiple mating in others remain enigmatic. In this study, I investigated whether queens of the wood ant Formica paralugubris adopting different dispersal strategies varied in their mating frequency (the number of males with whom they mated). The frequency of multiple mating was determined by using microsatellite markers to genotype the sperm stored in the spermatheca of queens, and the validity of this method was confirmed by analysing mother-offspring combinations obtained from experimental single-queen colonies. Dispersing queens, which may found new colonies, did not mate with more males than queens that stayed within polygynous colonies, where the presence of numerous reproductive individuals ensured a high level of genetic diversity. Hence, this study provides no support to the hypotheses that multiple mating is beneficial because it increases genetic variability within colonies. Most of the F. paralugubris queens mated with a single male, whatever their dispersal strategy and life history. Moreover, multiple mating had little effect on colony genetic structure: the effective mating frequency was 1.11 when calculated from within-brood relatedness, and 1.13 when calculated from the number of mates detected in the sperm. Hence, occasional multiple mating by F. paralugubris queens may have no adaptive significance.

Sex-chromosome differentiation parallels postglacial range expansion in European tree frogs (Hyla arborea).

Occasional XY recombination is a proposed explanation for the sex-chromosome homomorphy in European tree frogs. Numerous laboratory crosses, however, failed to detect any event of male recombination, and a detailed survey of NW-European Hyla arborea populations identified male-specific alleles at sex-linked loci, pointing to the absence of XY recombination in their recent history. Here, we address this paradox in a phylogeographic framework by genotyping sex-linked microsatellite markers in populations and sibships from the entire species range. Contrasting with postglacial populations of NW Europe, which display complete absence of XY recombination and strong sex-chromosome differentiation, refugial populations of the southern Balkans and Adriatic coast show limited XY recombination and large overlaps in allele frequencies. Geographically and historically intermediate populations of the Pannonian Basin show intermediate patterns of XY differentiation. Even in populations where X and Y occasionally recombine, the genetic diversity of Y haplotypes is reduced below the levels expected from the fourfold drop in copy numbers. This study is the first in which X and Y haplotypes could be phased over the distribution range in a species with homomorphic sex chromosomes; it shows that XY-recombination patterns may differ strikingly between conspecific populations, and that recombination arrest may evolve rapidly (<5000 generations).

Les natures mortes de Paul Gauguin: une production picturale méconnue

Gauguin's first attempts at still-life painting, around 1875, followed the Dutch tradition, influenced mainly by Manet's palette. But he did take occasional liberties in depicting flowers with more fluid colour and dynamic backgrounds. From 1879 his style shows the influence of the Impressionists: Pissarro in the landscapes and Degas in the composition of his still-lifes. He was also open to the new trends which were developing among artists in Paris and applied them in his paintings, using still-lifes as his main means for testing them. He did not escape the contemporary fascination with Japonism, and even experimented briefly with Pointillism in Still Life with Horse's Head. His stays in Britain between 1886 and 1890 correspond to an extremely rich and innovative period for him, in which still-lifes served for increasing experimentation. "Fête Gloanec" and Three Puppies reflect his preoccupations: rejection of perspective, use of areas of flat colour, and mixed styles. These pictures amount to an aesthetic manifesto; many of them are also imbued with strong symbolism, as in the Portrait of Meyer de Haan, which is a melancholic reflection on the fall of man. In Still-Life with Japanese Print, frail blue flowers seem to come out of the head of the artist-martyr, a pure product of the painter's "restless imagination". Thus Gauguin showed that art is an "abstraction" through a genre which was reputed to lend itself with difficulty to anything other than mimesis. Although he moved away from still-life after 1890, Gauguin is one of the first artists to radically renew its role and the status of still-life at the end of the 19th century, well before the Fauvists and Cubists.

A cryptic heterogametic transition revealed by sex-linked DNA markers in Palearctic green toads.

In sharp contrast to birds and mammals, most cold-blooded vertebrates have homomorphic (morphologically undifferentiated) sex chromosomes. This might result either from recurrent X-Y recombination (occurring e.g. during occasional events of sex reversal) or from frequent turnovers (during which sex-determining genes are overthrown by new autosomal mutations). Evidence for turnovers is indeed mounting in fish, but very few have so far been documented in amphibians, possibly because of practical difficulties in identifying sex chromosomes. Female heterogamety (ZW) has long been established in Bufo bufo, based on sex reversal and crossing experiments. Here, we investigate a sex-linked marker identified from a laboratory cross between Palearctic green toads (Bufo viridis subgroup). The F(1) offspring produced by a female Bufo balearicus and a male Bufo siculus were phenotypically sexed, displaying an even sex ratio. A sex-specific marker detected in highly reproducible AFLP genotypes was cloned. Sequencing revealed a noncoding, microsatellite-containing fragment. Reamplification and genotyping of families of this and a reciprocal cross showed B. siculus to be male heterogametic (XY) and suggested the same system for B. balearicus. Our results thus reveal a cryptic heterogametic transition within bufonid frogs and help explain patterns of hybrid fitness within the B. viridis subgroup. Turnovers of genetic sex-determination systems may be more frequent in amphibians than previously thought and thus contribute to the prevalence of homomorphic sex chromosomes in this group.

Geochemical study of vertebrate fossils from the Upper Cretaceous (Santonian) Csehbanya Formation (Hungary): Evidence for a freshwater habitat of mosasaurs and pycnodont fish

The diverse vertebrate remains from the Upper Cretaceous freshwater settings at Iharkut, Hungary, contain two fossil groups, Pycnodontiformes fish and Mosasauridae that are almost exclusively known from marine palaeo-environments. Hence, their appearance in alluvial sediments is very unusual. Trace element and isotope compositions of the remains have been analyzed to investigate the taphonomy and the ecological differences among the different fossil groups present at Iharkut. All examined fossils have undergone post-depositional diagenetic alteration, which resulted in high concentrations of REE, U, and Fe, together with almost complete homogenization of delta(18)O(CO3) values. Similar REE patterns in different fossils suggest a common origin for all remains, hence the discovered species most likely lived in the same local ecosystem. Despite partial diagenetic overprinting, the delta(18)O(PO4) values of the fossils indicate sufficient taxon-specific isotopic diversity to permit some broad conclusions on the palaeo-environment of the fossils. In particular, it is apparent that the isotopic composition of the Pycnodontiformes fish and Mosasauridae remains is most compatible with a freshwater palaeo-habitat and incompatible with a marine palaeo-environment. In addition, the Sr concentration and isotope data indicate that the Pycnodontiformes and Mosasauridae likely lived predominantly in a freshwater environment and were not simply occasional visitors to the Iharkut river ecosystem. Regarding other fossil groups, high delta(18)O(PO4) values of Alligatoroidea and Iharkutosuchus teeth suggest that these small crocodile species might have inhabited swamps and ponds where the water was relatively rich in (18)O due to evaporation. (c) 2009 Elsevier B.V. All rights reserved.

Bilateral anterior ischemic optic neuropathy following influenza vaccination.

Optic neuritis is an occasional complication of vaccination. Visual loss can be unilateral or bilateral, and most patients recover substantially without treatment. The presumptive mechanism is an immune-mediated demyelinating injury of the optic nerve. We report two patients who had permanent visual loss following influenza vaccination. Their pattern of visual loss, segmental optic disc changes, and failure of visual recovery were atypical for demyelinating optic neuritis and reminiscent of a primary ischemic injury to the optic nerve. We speculate that an immune complex-mediated vasculopathy following vaccination can cause anterior ischemic optic neuropathy. Clinicians should be aware of this entity because of the less favorable prognosis for visual recovery in these cases.

Guidelines for Cleaning up Former Methamphetamine Labs, June 2009

Methamphetamine (meth) drug labs are not a new hazard to Iowa. In 2004, federal, state and local authorities seized more than 1,400 Iowa labs. These labs are discovered in houses, apartments, motel rooms, motor vehicles, and even an occasional combine. A dramatic decrease in the number of meth labs occurred in 2005 when a law restricting the purchase of pseudo-ephedrine was implemented. Although the number of meth labs has decreased, they continue to exist. Since there is currently no official federal guidance or regulations on how to clean up a former meth lab, the Iowa Department of Public Health, Division of Environmental Health, has created these basic guidelines to assist public health officials, property owners and the general public in cleaning up former meth lab properties.

Magnetoencephalography demonstrates multiple asynchronous generators during human sleep spindles.

Sleep spindles are approximately 1 s bursts of 10-16 Hz activity that occur during stage 2 sleep. Spindles are highly synchronous across the cortex and thalamus in animals, and across the scalp in humans, implying correspondingly widespread and synchronized cortical generators. However, prior studies have noted occasional dissociations of the magnetoencephalogram (MEG) from the EEG during spindles, although detailed studies of this phenomenon have been lacking. We systematically compared high-density MEG and EEG recordings during naturally occurring spindles in healthy humans. As expected, EEG was highly coherent across the scalp, with consistent topography across spindles. In contrast, the simultaneously recorded MEG was not synchronous, but varied strongly in amplitude and phase across locations and spindles. Overall, average coherence between pairs of EEG sensors was approximately 0.7, whereas MEG coherence was approximately 0.3 during spindles. Whereas 2 principle components explained approximately 50% of EEG spindle variance, >15 were required for MEG. Each PCA component for MEG typically involved several widely distributed locations, which were relatively coherent with each other. These results show that, in contrast to current models based on animal experiments, multiple asynchronous neural generators are active during normal human sleep spindles and are visible to MEG. It is possible that these multiple sources may overlap sufficiently in different EEG sensors to appear synchronous. Alternatively, EEG recordings may reflect diffusely distributed synchronous generators that are less visible to MEG. An intriguing possibility is that MEG preferentially records from the focal core thalamocortical system during spindles, and EEG from the distributed matrix system.

Man-bites-dog business cycles

The newsworthiness of an event is partly determined by how unusual it isand this paper investigates the business cycle implications of this fact. In particular, weanalyze the consequences of information structures in which some types of signals are morelikely to be observed after unusual events. Such signals may increase both uncertainty anddisagreement among agents and when embedded in a simple business cycle model, can helpus understand why we observe (i) occasional large changes in macro economic aggregatevariables without a correspondingly large change in underlying fundamentals (ii) persistentperiods of high macroeconomic volatility and (iii) a positive correlation between absolutechanges in macro variables and the cross-sectional dispersion of expectations as measuredby survey data. These results are consequences of optimal updating by agents when theavailability of some signals is positively correlated with tail-events. The model is estimatedby likelihood based methods using individual survey responses and a quarterly time seriesof total factor productivity along with standard aggregate time series. The estimated modelsuggests that there have been episodes in recent US history when the impact on outputof innovations to productivity of a given magnitude was more than eight times as largecompared to other times.

Reduction of Concrete Deterioration by Ettringite Using Crystal Growth Inhibition Techniques: Part II Field Evaluation of Inhibitor Effectiveness, TR-469, 2004

The effects of diethylenetriaminpenta(methylenephosphonic acid) (DTPMP), a phosphonate inhibitor, on the growth of delayed ettringite have been evaluated using concrete in highway US 20 near Williams, Iowa, and the cores of six highways subject to moderate (built in 1992) or minor (built in 1997) deterioration. Application of 0.01 and 0.1 vol. % DTPMP to cores was made on a weekly or monthly basis for one year under controlled laboratory-based freeze-thaw and wet-dry conditions over a temperature range of -15 degrees to 58 degrees C to mimic extremes in Iowa roadway conditions. The same concentrations of phosphonate were also applied to cores left outside (roof of Science I at Iowa State University) over the same period of time. Nineteen applications of 0.1 vol. % DTPMP with added deicing salt solution (about 23 weight % NACL) were made to US 20 during the winters of 2003 and 2004. In untreated samples, air voids, pores, and occasional cracks are lined with acicular ettringite crystals (up to 50 micrometers in length) whereas air voids, pores, and cracks in concrete from the westbound lane of US 20 are devoid of ettringite up to a depth of about 0.5 mm from the surface of the concrete. Ettringite is also absent in zones up to 6 mm from the surface of concrete slabs placed on the roof of Science I and cores subject to laboratory-based freeze-thaw experiments. In these zones, the relatively high concentration of DTPMP caused it to behave as a chelator. Stunted ettringite crystals 5 to 25 micrometers in length, occasionally coated with porlandite, form on the margins of these zones indicating that in these areas DTPMP behaved as an inhibitor due to a reduction in the concentration of phosphonate. Analyses of mixes of ettringite and DTPMP using electrospray mass spectrometry suggests that the stunting of ettringite growth is caused by the adsorption of a Ca2+ ion and a water molecule to deprotonated DTPMP on the surface of the {0001} face of ettringite. It is anticipated that by using a DTPMP concentration of between 0.001 and 0.01 vol. % for the extended life of a highway (i.e. >20 years), deterioration caused by the expansive growth of ettringite will be markedly reduced.

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

Background Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. Methods An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability. Results Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models. Conclusions This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses.