Entitat Metropolitana del Transport. Centre Operatiu d'Autobusos del Prat

El projecte contempla la resolució d’un Centre Operatiu d’Autobusos Metropolitans amb un programa que ha de donar cabuda a un mínim de 300 places d’aparcament de diferents mesures, tallers de manteniment, túnels de neteja, sortidors de repostatge, vestuaris, administració, oficines i serveis generals. L’emplaçament se situa en el barri de Sant Cosme del Prat de Llobregat, en un solar que esdevé la façana d’aquesta població a l’entrada a Barcelona des de l’aeroport. L’entorn el conformen els espais de protecció de les pistes que es perllonguen fins a tocar el Parc Natural del Delta del Llobregat, una zona humida protegida d’àmbit europeu. Al mateix temps, els requeriments del concurs sol•liciten mantenir un 50% de la superfície del solar com a parc urbà. Això comporta abordar la resolució d’un edifici extens, però de 3 alçades i mitja, per tal de poder encabir tot el programa. Tot i així, la proposta integra el gran volum de l’edificació en harmonia compositiva i cromàtica amb el canyissar i manté l’alçària en una cota similar a la dels edificis de l’entorn. L’àrea verda es concentra en la part de la parcel•la que té continuïtat directe amb el pati del nou Esplai del barri, per tal de optimitzar-ne l’ús. Al mateix temps, les àrees de circulació, neteja i manteniment dels autobusos se situen a la part posterior del solar, per fer-les compatibles amb la resta de requeriments funcionals i perquè la volumetria principal doni front a les vies d’entrada a l’àrea metropolitana. La cotxera està continguda en un únic volum lleugerament soterrat, per limitar l’alçària total. La construcció principal, de 120 x 55 x 14,5 metres, es troba configurada per una estructura regular que respecta les mesures i moviments dels autobusos, i per una pell consistent en una gelosia oberta en tres cares, i tancada en l’alçat nord. Aquest tancament es realitza amb prismes verticals de colors similars a la vegetació del entorn, separats harmònicament per tal de dissoldre lleument els contorns del volum. Com a contrapunt a la gran peça principal, es proposa un petit edifici vidriat que indica l’entrada a les oficines i conté les activitats administratives.Les àrees de funcionament es resumeixen en les següents:1. La circulació dels autobusos: el conjunt disposa de tres vies simultànies, una d’accés i dues de sortida, situades en línia amb dos punts de repostatge, aspiració interior i traspàs de dades i recaptacions, aptes per a ser utilitzades per tres vehicles alhora. També es disposen tres túnels de rentat previs a l’entrada a l’interior de la cotxera, amb pas per a tres carrils en by-pass. Es preveu una quarta via especial d’accés i sortida directes al taller, per situacions extraordinàries.2. La circulació dels vehicles de personal: tenen un accés i un recorregut independent al dels autobusos, amb control informatitzat. 3. La entrada peatonal de visites o personal: l’edifici disposa també d’una entrada peatonal que es produeix des de la porta principal, situada en el front del edifici administratiu.4. El edifici principal: consta de diferents nivells. El Nivell 0, a cota –1,3 m. es troba ocupat per la zona d’aparcament de vehicles privats (98 uts), l’aparcament de minibusos (20 uts), el taller d’autobusos (23 uts standard amb ITV, 2 uts articulats, 1 ut pintura articulat, 2 uts reparcions sostres), i l’àrea d’explotació i de dependències per conductors (vestidors, àrea de descans, cafeteria i espais habitables).El Nivell 1, a cota 2,4 m. està ocupat per l’aparcament de 47 autobusos de 13 m. de llarg i per 20 autobusos de 15 m.El Nivell 2, a cota 4,8 m. l’ocupen 22 places d’autobusos de 15 m., 6 places d’articulats i 37 de 13 m.El Nivell 3, a cota 7,2 m. és idèntic al Nivell 1.El Nivell 4, és idèntic al Nivell 2 i permet que la rampa continuï fins a un Nivell 5 de coberta, que excepcionalment pot convertir-se en aparcament descobert de 67 autobusos de més.La proposta contempla amb fermesa criteris de Sostenibilitat. Aquests es centren en primer lloc en la sobrietat del projecte que garanteix una organització clara en quan a circulacions i rendiment del espai i que, per tant, no malbarata més recursos dels necessaris. En segon lloc, s’aprofiten al màxim la llum i la ventilació naturals i, al mateix temps, es genera la pròpia energia per millorar la eficiència. També es resol el re-processament dels residus generats pel complex, es re-aprofiten les aigües utilitzades en els vestuaris i oficines pel rentat dels vehicles, i s’emmagatzemen les aigües pluvials per tal de complementar la generació d’energia i per escalfar amb el sol aigua calenta de neteja. En tercer lloc, es té especial cura en l’impacte ambiental del edifici, procurant adequar-lo a l’estructura urbana tant en alineacions com el alçària. També s’evita la contaminació acústica apantallant el so intern per tal de no enviar-lo a les àrees habitades, s’endrecen els accessos dels autobusos des de la rotonda de la via pública per alterar el mínim el trànsit dels veïns, i es concentra l’àrea verda en la zona on es té més contacte amb l’activitat veïnal comunitària: l’Esplai del barri.

Quantum transport phenomena and shallow impurity states in CdSb

This work is dedicated to investigation of the energy spectrum of one of the most anisotropic narrow-gap semiconductors, CdSb. At the beginning of the present studies even the model of its energy band structure was not clear. Measurements of galvanomagnetic effects in wide temperature range (1.6 - 300 K) and in magnetic fields up to 30 T were chosen for clarifying of the energy spectrum in the intentionally undoped CdSb single crystals and doped with shallow impurities (In, Ag). Detection of the Shubnikov - de Haas oscillations allowed estimating the fundamental energy spectrum parameters. The shapes of the Fermi surfaces of electrons (sphere) and holes (ellipsoid), the number of the equivalent extremums for valence band (2) and their positions in the Brillouin zone were determined for the first time in this work. Also anisotropy coefficients, components of the tensor of effective masses of carriers, effective masses of density of states, nonparabolicity of the conduction and valence bands, g-factor and its anisotropy for n- and p-CdSb were estimated for the first time during these studies. All the results obtained are compared with the cyclotron resonance data and the corresponding theoretical calculations for p-CdSb. This is basic information for the analyses of the complex transport properties of CdSb and for working out the energy spectrum model of the shallow energy levels of defects and impurities in this semiconductor. It was found out existence of different mechanisms of hopping conductivity in the presence of metal - insulator transition induced by magnetic field in n- and p-CdSb. Quite unusual feature opened in CdSb is that different types of hopping conductivity may take place in the same crystal depending on temperature, magnetic field or even orientation of crystal in magnetic field. Transport properties of undoped p-CdSb samples show that the anisotropy of the resistivity in weak and strong magnetic fields is determined completely by the anisotropy of the effective mass of the holes. Temperature and magnetic field dependence of the Hall coefficient and magnetoresistance is attributed to presence of two groups of holes with different concentrations and mobilities. The analysis demonstrates that below Tcr ~ 20 K and down to ~ 6 - 7 K the low-mobile carriers are itinerant holes with energy E2 ≈ 6 meV. The high-mobile carriers, at all temperatures T < Tcr, are holes activated thermally from a deeper acceptor band to itinerant states of a shallower acceptor band with energy E1 ≈ 3 meV. Analysis of temperature dependences of mobilities confirms the existence of the heavy-hole band or a non-equivalent maximum and two equivalent maxima of the light-hole valence band. Galvanomagnetic effects in n-CdSb reveal the existence of two groups of carriers. These are the electrons of a single minimum in isotropic conduction band and the itinerant electrons of the narrow impurity band, having at low temperatures the energies above the bottom of the conduction band. It is found that above this impurity band exists second impurity band of only localized states and the energy of both impurity bands depend on temperature so that they sink into the band gap when temperature is increased. The bands are splitted by the spin, and in strong magnetic fields the energy difference between them decreases and redistribution of the electrons between the two impurity bands takes place. Mobility of the conduction band carriers demonstrates that scattering in n-CdSb at low temperatures is strongly anisotropic. This is because of domination from scattering on the neutral impurity centers and increasing of the contribution to mobility from scattering by acoustic phonons when temperature increases. Metallic conductivity in zero or weak magnetic field is changed to activated conductivity with increasing of magnetic field. This exhibits a metal-insulator transition (MIT) induced by the magnetic field due to shift of the Fermi level from the interval of extended states to that of the localized states of the electron spectrum near the edge of the conduction band. The Mott variablerange hopping conductivity is observed in the low- and high-field intervals on the insulating side of the MIT. The results yield information about the density of states, the localization radius of the resonant impurity band with completely localized states and about the donor band. In high magnetic fields this band is separated from the conduction band and lies below the resonant impurity bands.

Brain glucose sensing and neural regulation of insulin and glucagon secretion.

Glucose homeostasis requires the tight regulation of glucose utilization by liver, muscle and white or brown fat, and glucose production and release in the blood by liver. The major goal of maintaining glycemia at ∼ 5 mM is to ensure a sufficient flux of glucose to the brain, which depends mostly on this nutrient as a source of metabolic energy. This homeostatic process is controlled by hormones, mainly glucagon and insulin, and by autonomic nervous activities that control the metabolic state of liver, muscle and fat tissue but also the secretory activity of the endocrine pancreas. Activation or inhibition of the sympathetic or parasympathetic branches of the autonomic nervous systems are controlled by glucose-excited or glucose-inhibited neurons located at different anatomical sites, mainly in the brainstem and the hypothalamus. Activation of these neurons by hyper- or hypoglycemia represents a critical aspect of the control of glucose homeostasis, and loss of glucose sensing by these cells as well as by pancreatic β-cells is a hallmark of type 2 diabetes. In this article, aspects of the brain-endocrine pancreas axis are reviewed, highlighting the importance of central glucose sensing in the control of counterregulation to hypoglycemia but also mentioning the role of the neural control in β-cell mass and function. Overall, the conclusions of these studies is that impaired glucose homeostasis, such as associated with type 2 diabetes, but also defective counterregulation to hypoglycemia, may be caused by initial defects in glucose sensing.

Glucagon-like peptide-1 increases beta-cell glucose competence and proliferation by translational induction of insulin-like growth factor-1 receptor expression.

Glucagon-like peptide-1 (GLP-1) protects beta-cells against apoptosis, increases their glucose competence, and induces their proliferation. We previously demonstrated that the anti-apoptotic effect was mediated by an increase in insulin-like growth factor-1 receptor (IGF-1R) expression and signaling, which was dependent on autocrine secretion of insulin-like growth factor 2 (IGF-2). Here, we further investigated how GLP-1 induces IGF-1R expression and whether the IGF-2/IGF-1R autocrine loop is also involved in mediating GLP-1-increase in glucose competence and proliferation. We show that GLP-1 up-regulated IGF-1R expression by a protein kinase A-dependent translational control mechanism, whereas isobutylmethylxanthine, which led to higher intracellular accumulation of cAMP than GLP-1, increased both IGF-1R transcription and translation. We then demonstrated, using MIN6 cells and primary islets, that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF-2 secretion. We showed that GLP-1-induced primary beta-cell proliferation was suppressed by Igf-1r gene inactivation and by IGF-2 immunoneutralization or knockdown. Together our data show that regulation of beta-cell number and function by GLP-1 depends on the cAMP/protein kinase A mediated-induction of IGF-1R expression and the increased activity of an IGF-2/IGF-1R autocrine loop.

Metabolism of oral glucose in children born small for gestational age : evidence for an impaired whole body glucose oxidation

Résumé Les études épidémiologiques indiquent que la restriction intra-utérine confère un risque accru de développement de diabète de type 2 au cours de la vie. Certaines études ont documenté la présence d'une résistance à l'insuline chez les jeunes adultes ou les adolescents nés petits pour l'âge gestationnel. Comme la plupart des études ont impliqués des individus post-pubères et comme la puberté influence de manière marquée le métabolisme énergétique, nous avons évalué le devenir du glucose administré oralement dans un groupe incluant essentiellement des enfants pré-pubères ou en début de puberté avec restriction intra-utérine, et chez des enfants matchés pour l'âge et pour le poids. Tous les enfants ont eu une évaluation de leur composition corporelle par mesure des plis cutanés. Ils ont ensuite été étudiés dans des conditions standardisées et ont reçu 4 charges consécutives orales de glucose à raison de 180 mg/kg de poids corporel jusqu'à atteindre un état d'équilibre relatif. La dépense énergétique et l'oxydation des substrats ont été évaluées durant la quatrième heure par calorimétrie indirecte. Comparativement avec les enfants matchés pour l'âge et le poids, les enfants nés petits pour l'âge gestationnel avaient une plus petite stature. Leur dépense énergétique n'était pas significativement abaissée, mais leur oxydation du glucose était plus basse. Ces résultats indiquent que des altérations métaboliques sont présentes précocement chez les enfants nés petits pour l'âge gestationnel, et qu'elles sont possiblement reliées à des altérations de la composition corporelle. Abstract: Epidemiological studies indicate that intrauterine growth restriction confers an increased risk of developing type 2 diabetes mellitus in subsequent life. Several studies have further documented the presence of insulin resistance in young adults or adolescent children born small for gestational age. Since most studies addressed postpubertal individuals, and since puberty markedly affects energy metabolism, we evaluated the disposal of oral glucose in a group including mainly prepubertal and early pubertal children with intrauterine growth restriction and in healthy age- and weight-matched control children. All children had an evaluation of their body composition by skinfold thickness measurements. They were then studied in standardized conditions and received 4 consecutive hourly loads of 180 mg glucose/kg body weight to reach a near steady state. Energy expenditure and substrate oxidation were evaluated during the fourth hour by indirect calorimetry. Compared to both age- and weight-matched children, children born small for gestational age had lower stature. Their energy expenditure was not significantly decreased, but they had lower glucose oxidation rates. These results indicate that metabolic alterations are present early in children born small for gestational age, and are possibly related to alterations of body composition.

Intracellular targeting of GLUT4 in transfected insulinoma cells: evidence for association with constitutively recycling vesicles distinct from synaptophysin and insulin vesicles.

In adipocytes and muscle cells, the GLUT4 glucose transporter isoform is present in intracellular vesicles which continuously recycle between an intracytoplasmic location and the plasma membrane. It is not clear whether the GLUT4-vesicles represent a specific kind of vesicle or resemble typical secretory granules or synaptic-like microvesicles. To approach this question, we expressed GLUT4 in the beta cell line RINm5F and determined its intracellular localization by subcellular fractionation and by immunofluorescence and immunoelectron microscopy. GLUT4 was not found in insulin granules but was associated with a subpopulation of smooth-surface vesicles present in the trans-Golgi region and in vesicular structures adjacent to the plasma membrane. In the trans-Golgi region, GLUT4 did not colocalize with synaptophysin or TGN38. Incubation of the cells with horseradish peroxidase (HRP) led to colocalization of HRP and GLUT4 in some endosomal structures adjacent to the plasma membrane and in occasional trans-Golgi region vesicles. When cells were incubated in the presence of Bafilomycin A, analysis by confocal microscopy revealed GLUT4 in numerous large spots present throughout the cytoplasm, many of which costained for TGN38 and synaptophysin. By immunoelectron microscopy, numerous endosomes were observed which stained strongly for GLUT4. Together our data demonstrate that ectopic expression of GLUT4 in insulinoma cells reveals the presence of a subset of vesicular structures distinct from synaptic-like vesicles and insulin secretory granules. Furthermore, they indicate that GLUT4 constitutively recycles between the plasma membrane and its intracellular location by an endocytic route also taken by TGN38 and synaptophysin.

Volcanic debris avalanche deposits of the upper Maronne valley (Cantal Volcano, France): evidence for contrasted formation and transport mechanisms

The deposits of two volcanic debris avalanches (VDA I and II) that occur in the upper Maronne valley, northwest sector of Cantal Volcano, France, were studied to establish their mechanisms of formation, transport and deposition. These two volcanic debris avalanches that clearly differ with regard to their structures, textures and extensions, exemplify the wide spectrum of events associated with large-scale sector collapse. VDA I is voluminous (similar to1 km(3) in the upper Maronne valley) and widespread. The deposits comprise two distinct facies: the block facies that forms the intermediate and upper part of the unit and the mixed facies that crops out essentially at the base of the unit. The block facies consists of more or less brecciated lava, block-and-ash-flow breccia and pumice-flow tuff megablocks set in breccias resulting from block disaggregation. Mixing and differential movements are almost absent in this part of the VDA. The mixed facies consists of breccias rich in fine particles that originate from block disagregation, as well as being picked up from the substratum during movement. Mixing and differential movements are predominant in this zone. Analysis of fractures on lava megablocks suggests that shear stress during the initial sliding is the principal cause of fracture. These data strongly indicate that VDA I is purely gravitational and argue for a model in which the initial sliding mass transforms into a flow due to differential in situ fragmentation caused by the shear stress. VDA II is restricted to low-topography areas. Its volume, in the studied area, is about 0.3 km(3). The deposits consist of brecciated, rounded blocks and megablocks set in a fine-grained matrix composed essentially of volcanic glass. This unit is stratified, with a massive layer that contains all the megablocks at the base and in the intermediate part, and in the upper part a normally graded layer that contains only blocks <1 m in size. The different lithologies present are totally mixed. These observations suggest that VDA II may be of the Bezymianny-type and that it underwent a flow transformation from a turbulent to a stratified flow consisting of a basal hyperconcentrated laminar body overlain by a dilute layer. (C) 2000 Elsevier Science B.V. All rights reserved.

Determination of salivary glucose in healthy adults

Objectives: Our aim in this study was to determine the concentration of salivary glucose in healthy individuals and to compare it with the capillary glycemia. Study design: Samples of unstimulated whole saliva were collected from 63 non-diabetic patients. The concentration of salivary glucose and capillary blood was measured in all of the patients. The salivary glucose was determined by enzymatic method and spectrophotometry. The data was then analyzed using the Spearman correlation test, considering values of p<0.05 to be significant. Results: The whole sample consisted of 47.6% males and 52.4% women, with an average age of 37.5±15.7 years old. The average rates of unstimulated salivary flow were 0.41±0.21 ml/min among males and 0.31±0.15 ml/min among females. No significant difference was found based on these results (p=0.078). The average blood glucose among the males studied was 100.05±13.51 mg/dL, and among females, it was 99.5±13.9 mg/dL. The average salivary glucose for the whole sample was 5.97±1.87 mg/dL, with 5.91±2.19 mg/dL among males and 5.97±1.56 mg/dL among females, respectively, without presenting any significant differences (p=0.908). The concentration of salivary glucose did not present any statistically significant correlation with the capillary glycemia (p=0.732). Conclusions: The results suggest that the concentration of salivary glucose is not dependent on capillary glycemia and that the concentration of salivary glucose does not present significant differences between the measurements for males and females.

When supply travels far beyond demand: Causes of oversupply in Spain’s transport infrastructure

Spain’s transport infrastructure policy has become a paradigmatic case of oversupply and of mismatch with demand. The massive expansion of the country’s transport infrastructure over the last decade has not been a response to demand bottlenecks or previously identified needs. For this reason, the intensity of use today on all interurban modes of transport in Spain falls well below that of other EU countries. This paper analyzes the institutional and regulatory factors that have permitted this policy, allowing us to draw lessons from the Spanish case that should help other countries avoid the pitfalls and shortcomings of Spanish policy.

When supply travels far beyond demand: Causes of oversupply in Spain’s transport infrastructure

Spain’s transport infrastructure policy has become a paradigmatic case of oversupply and of mismatch with demand. The massive expansion of the country’s transport infrastructure over the last decade has not been a response to demand bottlenecks or previously identified needs. For this reason, the intensity of use today on all interurban modes of transport in Spain falls well below that of other EU countries. This paper analyzes the institutional and regulatory factors that have permitted this policy, allowing us to draw lessons from the Spanish case that should help other countries avoid the pitfalls and shortcomings of Spanish policy.

Glutamate reduces glucose utilization while concomitantly enhancing AQP9 and MCT2 expression in cultured rat hippocampal neurons.

The excitatory neurotransmitter glutamate has been reported to have a major impact on brain energy metabolism. Using primary cultures of rat hippocampal neurons, we observed that glutamate reduces glucose utilization in this cell type, suggesting alteration in mitochondrial oxidative metabolism. The aquaglyceroporin AQP9 and the monocarboxylate transporter MCT2, two transporters for oxidative energy substrates, appear to be present in mitochondria of these neurons. Moreover, they not only co-localize but they interact with each other as they were found to co-immunoprecipitate from hippocampal neuron homogenates. Exposure of cultured hippocampal neurons to glutamate 100 μM for 1 h led to enhanced expression of both AQP9 and MCT2 at the protein level without any significant change at the mRNA level. In parallel, a similar increase in the protein expression of LDHA was evidenced without an effect on the mRNA level. These data suggest that glutamate exerts an influence on neuronal energy metabolism likely through a regulation of the expression of some key mitochondrial proteins.

Thermogenesis in obese women: effect of fructose vs. glucose added to a meal.

To assess the effect of a fructose meal on resting energy expenditure (EE), indirect calorimetry was used in 23 women (10 lean and 13 obese) for 30 min before and 6 h after the ingestion of a mixed meal containing 20% protein, 33% fat, and either 75 g glucose or 75 g fructose as carbohydrate source (47%). Expressed as a percentage of the energy content of the meal, the thermogenic response to the fructose meal was significantly greater (10.2 +/- 0.5%) than that of the glucose meal (8.4 +/- 0.4%, P less than 0.01). This difference was still apparent when the lean and obese women were considered separately. The mean respiratory quotient during the 6-h postprandial period was significantly greater (P less than 0.01) for the fructose (0.85 +/- 0.01) than for the glucose meal (0.83 +/- 0.01) in the combined subjects. In addition, cumulative carbohydrate oxidation was significantly greater after the fructose than after the glucose meal (51.1 +/- 2.3 vs. 40.9 +/- 2.0 g/6 h, respectively, P less than 0.01). Only small changes were observed in postprandial plasma levels of glucose and insulin after the fructose meal, but the plasma levels of lactate increased more with fructose than with the glucose meal. These results suggest that there might be some advantages (higher thermogenesis and carbohydrate oxidations) in using fructose as part of the carbohydrate source in diet of people with obesity and/or insulin resistance.

Evolution of the epithelial sodium channel and the sodium pump as limiting factors of aldosterone action on sodium transport.

Despite large changes in salt intake, the mammalian kidney is able to maintain the extracellular sodium concentration and osmolarity within very narrow margins, thereby controlling blood volume and blood pressure. In the aldosterone-sensitive distal nephron (ASDN), aldosterone tightly controls the activities of epithelial sodium channel (ENaC) and Na,K-ATPase, the two limiting factors in establishing transepithelial sodium transport. It has been proposed that the ENaC/degenerin gene family is restricted to Metazoans, whereas the α- and β-subunits of Na,K-ATPase have homologous genes in prokaryotes. This raises the question of the emergence of osmolarity control. By exploring recent genomic data of diverse organisms, we found that: 1) ENaC/degenerin exists in all of the Metazoans screened, including nonbilaterians and, by extension, was already present in ancestors of Metazoa; 2) ENaC/degenerin is also present in Naegleria gruberi, an eukaryotic microbe, consistent with either a vertical inheritance from the last common ancestor of Eukaryotes or a lateral transfer between Naegleria and Metazoan ancestors; and 3) The Na,K-ATPase β-subunit is restricted to Holozoa, the taxon that includes animals and their closest single-cell relatives. Since the β-subunit of Na,K-ATPase plays a key role in targeting the α-subunit to the plasma membrane and has an additional function in the formation of cell junctions, we propose that the emergence of Na,K-ATPase, together with ENaC/degenerin, is linked to the development of multicellularity in the Metazoan kingdom. The establishment of multicellularity and the associated extracellular compartment ("internal milieu") precedes the emergence of other key elements of the aldosterone signaling pathway.

Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment.

OBJECTIVE: To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. METHOD: [¹⁸F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. RESULTS: The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. CONCLUSION: The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

The Lin28/let-7 axis regulates glucose metabolism.

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.