Impaired nutrient signaling and body weight control in a Na⁺ neutral amino acid cotransporter (Slc6a19)-deficient mouse

Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter BᴼAT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Na⁺ -dependent uptake of neutral amino acids into the intestine and renal brush-border membrane vesicles was abolished. No compensatory increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking BᴼAT1 showed a reduced body weight. When adapted to a standard 20% protein diet, BᴼAT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.This work was supported by National Health and Medical Research Council Grant 525415, Australian Research Council Grant DP0877897, University of Sydney Bridging Grant RIMS2009-02579), and by an anonymous foundatio

A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion

10.1371/journal.ppat.1003297PLoS Pathogens94

Altered language network activity in young people at familial high-risk for schizophrenia

Background—Abnormalities in language and language neural circuitry are observed in schizophrenia (SZ). Similar, but less pronounced language deficits are also seen in young first degree relatives of people with SZ, who are at higher familial risk (FHR) for the disorder than the general population. The neural underpinnings of these deficits in people with FHR are unclear. Methods—Participants were 43 people with FHR and 32 comparable controls. fMRI scans were collected while participants viewed associated and unrelated word pairs, and performed a lexical decision task. fMRI analyses conducted in SPM8 examined group differences in the modulation of hemodynamic activity by semantic association. Results—There were no group differences in demographics, IQ or behavioral semantic priming, but FHR participants had more schizotypal traits than controls. Controls exhibited the expected suppression of hemodynamic activity to associated versus unrelated word pairs. Compared to controls, FHR participants showed an opposite pattern of hemodynamic modulation to associated versus unrelated word pairs, in the left inferior frontal gyrus (IFG), right superior and middle temporal gyrus (STG) and the left cerebellum. Group differences in activation were significant, FWE-corrected for multiple comparisons (p<0.05). Activity within the IFG during the unrelated condition predicted schizotypal symptoms in FHR participants. Conclusions—FHR for SZ is associated with abnormally increased neural activity to semantic associates within an inferior frontal/temporal network. This might increase the risk of developing unusual ideas, perceptions and disorganized language that characterize schizotypal traits, potentially predicting which individuals are at greater risk to develop a psychotic disorder

The economic burden of bronchiectasis - known and unknown:a systematic review

Abstract Background The increasing prevalence and recognition of bronchiectasis in clinical practice necessitates a better understanding of the economic disease burden to improve the management and achieve better clinical and economic outcomes. This study aimed to assess the economic burden of bronchiectasis based on a review of published literature. Methods A systematic literature review was conducted using MEDLINE, Embase, EconLit and Cochrane databases to identify publications (1 January 2001 to 31 December 2016) on the economic burden of bronchiectasis in adults. Results A total of 26 publications were identified that reported resource use and costs associated with management of bronchiectasis. Two US studies reported annual incremental costs of bronchiectasis versus matched controls of US$5681 and US$2319 per patient. Twenty-four studies reported on hospitalization rates or duration of hospitalization for patients with bronchiectasis. Mean annual hospitalization rates per patient, reported in six studies, ranged from 0.3–1.3, while mean annual age-adjusted hospitalization rates, reported in four studies, ranged from 1.8–25.7 per 100,000 population. The average duration of hospitalization, reported in 12 studies, ranged from 2 to 17 days. Eight publications reported management costs of bronchiectasis. Total annual management costs of €3515 and €4672 per patient were reported in two Spanish studies. Two US studies reported total costs of approximately US$26,000 in patients without exacerbations, increasing to US$36,00–37,000 in patients with exacerbations. Similarly, a Spanish study reported higher total annual costs for patients with > 2 exacerbations per year (€7520) compared with those without exacerbations (€3892). P. aeruginosa infection increased management costs by US$31,551 to US$56,499, as reported in two US studies, with hospitalization being the main cost driver. Conclusions The current literature suggests that the economic burden of bronchiectasis in society is significant. Hospitalization costs are the major driver behind these costs, especially in patients with frequent exacerbations. However, the true economic burden of bronchiectasis is likely to be underestimated because most studies were retrospective, used ICD-9-CM coding to identify patients, and often ignored outpatient burden and cost. We present a conceptual framework to facilitate a more comprehensive assessment of the true burden of bronchiectasis for individuals, healthcare systems and society

Chemotactic and Inflammatory Responses in the Liver and Brain Are Associated with Pathogenesis of Rift Valley Fever Virus Infection in the Mouse

Rift Valley fever virus (RVFV) is a major human and animal pathogen associated with severe disease including hemorrhagic fever or encephalitis. RVFV is endemic to parts of Africa and the Arabian Peninsula, but there is significant concern regarding its introduction into non-endemic regions and the potentially devastating effect to livestock populations with concurrent infections of humans. To date, there is little detailed data directly comparing the host response to infection with wild-type or vaccine strains of RVFV and correlation with viral pathogenesis. Here we characterized clinical and systemic immune responses to infection with wild-type strain ZH501 or IND vaccine strain MP-12 in the C57BL/6 mouse. Animals infected with live-attenuated MP-12 survived productive viral infection with little evidence of clinical disease and minimal cytokine response in evaluated tissues. In contrast, ZH501 infection was lethal, caused depletion of lymphocytes and platelets and elicited a strong, systemic cytokine response which correlated with high virus titers and significant tissue pathology. Lymphopenia and platelet depletion were indicators of disease onset with indications of lymphocyte recovery correlating with increases in G-CSF production. RVFV is hepatotropic and in these studies significant clinical and histological data supported these findings; however, significant evidence of a pro-inflammatory response in the liver was not apparent. Rather, viral infection resulted in a chemokine response indicating infiltration of immunoreactive cells, such as neutrophils, which was supported by histological data. In brains of ZH501 infected mice, a significant chemokine and pro-inflammatory cytokine response was evident, but with little pathology indicating meningoencephalitis. These data suggest that RVFV pathogenesis in mice is associated with a loss of liver function due to liver necrosis and hepatitis yet the long-term course of disease for those that might survive the initial hepatitis is neurologic in nature which is supported by observations of human disease and the BALB/c mouse model

Microscopic dynamics of granular materials

In the present dissertation, the motion of inelastic spheres on a rough inclined plane is investigated by means of numerical simulations. In a special case, a theoretical model for the motion is presented as well. After an overview of the physics of granular media and a brief outline of existing theoretical models and their limits, the simulation methods used in the present work are explained, where the focus is on time-step driven and event driven molecular dynamics. Advantages and disadvantages are discussed, as well as possible artifacts. In time-step driven molecular dynamics simulations the contact forces acting between particles have to be specified. Since there is no generally accepted force model available for granular materials, a number of common force models is investigated by simulations of simple sample systems. These simulations are compared with experiments (binary collision of spheres) and analytical results (a cylinder pushed along a plane by a block). It is shown that some force laws exhibit unphysical behaviour. In some, though not all, of these cases, possibilities to evite these problems by simple physically motivated modifications are presented. The central part of this work deals with the motion of a sphere on a rough inclined plane. By means of molecular dynamics simulations the mechanisms leading to a steady state and its limits are investigated. It turns out that this mechanism leads to independence of the mean steady state velocity of material parameters like the normal restitution coefficient and the coefficient of friction. Based on this observation, a simplified and analytically solvable model for the motion in two dimensions is presented which approximates the steady state velocity and the lower limit of the steady state very well276 refs.SIGLEAvailable from TIB Hannover: RA 831(3510) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Schallausbreitung in granularen Medien

Various physical properties of granular packing structure have been considered. The following topics were dealt with: modelling of granular grain interactions, hard sphere collision interactions, inelastic interactions, friction effects, computer simulation of sound propagation in granular materials, sound propagation along a linear chain of monodispersive particles, generalization of the Hertz mechanical contact law, nonlinear effects in a Toda oscillator chain, solitons, properties of static ganular packing143 refs.SIGLEAvailable from TIB Hannover: RA 831(3161) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Untersuchung von atomarem und molekularem Wasserstoff vor einer Graphitoberflaeche in einem Hochtemperatur-Randschichtplasma

The purpose of this work is a global characterisation of the neutral species which are set free from a graphite surface during the hydrogen recycling process. The emphasis was put on the isotope deuterium. Besides the question of the type of the surface-released species - atomic or molecular - and their characteristics - velocity distribution, penetration depth, population etc. -, the investigations were focused on the determination of the entire deuterium particle flux. For the first time, a quantification was carried out via the simultaneous absolute determination of the particle fluxes of the atoms and molecules involved. In order to probe deuterium, a special measurement arrangement was used, which enabled the simultaneous observation by means of five spectroscopic systems. Additionally, another active system was attached to the measuring arrangement in order to determine the local velocity distribution and density of the atoms in the ground state by means of LIF at L_#alpha#. All diagnostics were used in situ in front of a limiter in the plasma edge of TEXTOR over the entire accessible parameter range n_e=1 x 10&quot;1&quot;8-1.5 x 10&quot;1&quot;9 m&quot;-&quot;3, T_e=30-100 eV. The molecules contribute 90% to the total deuteron flux in the case of low surface temperatures. The remaining 10% of the total flux result from the contribution of mainly reflected particles. In contrast, the release took place via thermal atoms only, in the case of a heated surface. With knowledge of the ratio of atoms to molecules, a correction for the factor S/XB could be determined. It permitted the determination of the total deuterium particle flux from the measurement of the Balmer-#alpha# photon flux with consideration of the molecules. Both with passive and active spectroscopy the presence of so-called cold or low-energy atoms (&lt; 1 eV) was confirmed. It is assumed that they have their origin in the high number of molecules and molecular ions in the boundary layer. In order to clarify the reaction mechanism, further measurements with LIF and modelling with the neutral particle code EIRENE will be necessary. (orig.)Available from TIB Hannover: RA 831(3962) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Die Temperaturabhaengigkeit elektrischer Eigenschaften von Festelektrolyten und elektrochemischer Reaktionen

The electrical properties of electrolytes and the electrochemical behavior of the electrode - electrolyte interface were investigated experimentally and theoretically using liquid and solid electrolytes of identical composition. The polyhydrates HClO_4.5.5 H_2O, DClO_4.5.5 D_2O and HBF_4.5.75 H_2O are acid components which solidify in a type I clathrate structure consisting of a host lattice formed by the water molecules and anionic guest species. (NMR measurements showed that the protons are the mobile species in the clathrate system.) Using the FREECE-(Frozen Electrolyte Electrochemistry)-technique, it is possible to investigate experimentally the electrical and electrochemical behavior of such systems in a wide range of temperatures. (orig./WL)88 refs.Available from TIB Hannover: RA 831(3128) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman