Prenatal and postnatal maternal contributions in the infection model of schizophrenia

Epidemiological studies have indicated that the risk of schizophrenia is enhanced by prenatal maternal infection with viral or bacterial pathogens. Recent experimentation in rodents has yielded additional support for a causal relationship between prenatal immune challenge and the emergence of psychosis-related abnormalities in brain and behaviour in later life. However, little is known about the putative roles of maternal postnatal factors in triggering and modulating the emergence of psychopathology following prenatal immunological stimulation. Here, we aimed to dissect the relative contributions of prenatal inflammatory events and postnatal maternal factors in precipitating juvenile and adult psychopathology in the resulting offspring with a cross-fostering design. Pregnant mice were exposed to the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 5mg/kg, intravenously), or vehicle treatment on gestation day 9, and offspring born to PolyI:C- and vehicle-treated dams were then simultaneously cross-fostered to surrogate rearing mothers, which had either experienced inflammatory or vehicle treatment during pregnancy. Prenatal PolyI:C administration did not affect the expression of latent inhibition (LI) at a juvenile stage of development, but led to the post-pubertal emergence of LI disruption in both aversive classical and instrumental conditioning regardless of the postnatal rearing condition. In addition, deficits in conditioning as such led to a pre- and post-pubertal loss of LI in prenatal control animals that were adopted by PolyI:C-treated surrogate mothers. Our findings thus indicate that the adoption of prenatally immune-challenged neonates by control surrogate mothers does not possess any protective effects against the subsequent emergence of psychopathology in adulthood. At the same time, however, the present study highlights for the first time that the adoption of prenatal control animals by immune-challenged rearing mothers is sufficient to precipitate learning disabilities in the juvenile and adult offsprin

Deficient maternal care resulting from immunological stress during pregnancy is associated with a sex-dependent enhancement of conditioned fear in the offspring

Activation of maternal stress response systems during pregnancy has been associated with altered postpartum maternal care and subsequent abnormalities in the offspring’s brain and behavioral development. It remains unknown, however, whether similar effects may be induced by exposure to immunological stress during pregnancy. The present study was designed to address this issue in a mouse model of prenatal immune activation by the viral mimic polyriboinosinic–polyribocytidilic acid (PolyI:C). Pregnant mice were exposed to PolyI:C-induced immune challenge or sham treatment, and offspring born to PolyI:C- and sham-treated dams were simultaneously cross-fostered to surrogate rearing mothers, which had either experienced inflammatory or vehicle treatment during pregnancy. We evaluated the effects of the maternal immunological manipulation on postpartum maternal behavior, and we assessed the prenatal and postnatal maternal influences on anxiety- and fear-related behavior in the offspring at the peri-adolescent and adult stage of development. We found that PolyI:C treatment during pregnancy led to changes in postpartum maternal behavior in the form of reduced pup licking/grooming and increased nest building activity. Furthermore, the adoption of neonates by surrogate rearing mothers, which had experienced PolyI:C-induced immunological stress during pregnancy, led to enhanced conditioned fear in the peri-adolescent and adult offspring, an effect that was exclusively seen in female but not male subjects. Unconditioned (innate) anxiety-related behavior as assessed in the elevated plus maze and open field explorations tests were not affected by the prenatal and postnatal manipulations. Our results thus highlight that being raised by gestationally immune-challenged surrogate mothers increases the vulnerability for specific forms of fear-related behavioral pathology in later life, and that this association may be mediated by deficits in postpartum maternal care. This may have important implications for the identification and characterization of early-life risk factors involved in the developmental etiology of fear-related neuropsychiatric disorders

Experimental characterization of cement–bentonite interaction using core infiltration techniques and 4D computed tomography

Deep geological storage of radioactive waste foresees cementitious materials as reinforcement of tunnels and as backfill. Bentonite is proposed to enclose spent fuel drums, and as drift seals. The emplacement of cementitious material next to clay material generates an enormous chemical gradient in pore water composition that drives diffusive solute transport. Laboratory studies and reactive transport modeling predict significant mineral alteration at and near interfaces, mainly resulting in a decrease of porosity in bentonite. The goal of this project is to characterize and quantify the cement/bentonite skin effects spatially and temporally in laboratory experiments. A newly developed mobile X-ray transparent core infiltration device was used, which allows performing X-ray computed tomography (CT) periodically without interrupting a running experiment. A pre-saturated cylindrical MX-80 bentonite sample (1920 kg/m3 average wet density) is subjected to a confining pressure as a constant total pressure boundary condition. The infiltration of a hyperalkaline (pH 13.4), artificial OPC (ordinary Portland cement) pore water into the bentonite plug alters the mineral assemblage over time as an advancing reaction front. The related changes in X-ray attenuation values are related to changes in phase densities, porosity and local bulk density and are tracked over time periodically by non-destructive CT scans

Prenatal and postnatal maternal contributions in the infection model of schizophrenia

ISSN:0014-4819ISSN:1432-110

Rheological and stability aspects of dry and hydrothermally heat treated aleurone-rich wheat milling fraction

Novel aleurone-rich wheat milling fraction developed and produced on industry scale is investigated. The special composition of the novel flour with high protein, dietary fiber and fat content results in a unique combination of the mixing and viscosity properties. Due to the high lipid concentration, the fraction is exposed to fast rancidity. Dry heat (100 °C for 12 min) and hydrothermal treatment processes (96 °C for 6 min with 0–20 L/h steam) were applied on the aleurone-rich flour to modify the technological properties. The chemical, structural changes; the extractability of protein, carbohydrate and phenolic components and the rheological characteristics of the flours were evaluated. The dry treated flour decreased protein and carbohydrate extractability, shortened dough development time, reduced gel strength and enhanced the gelling ability. Hydrothermal treatment caused changes in the phenolic content improved the dough stability and -resistance. Heat treatment processes were able to extend the stability of the flour

Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects

Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H+-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals

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Niclosamide neutralizes acidic liposomal pH similar as the protein gradient uncoupling agents DNP or CCCP.

<p>A). 200 nm sized liposomes were prepared in presence of dextran-FITC (1 mM, 4.4 kDa) at pH 5.15 (top panel), which quenches FITC-fluorescence and dequenched by the protonophoric action of niclosamide, 2,4-DNP (2,4-di-nitrophenol) or m-CCCP (m-chlorophenylhydrazone). The integrity of liposomes upon treatment is shown as mean vesicle size (insert bar-graph). B). Model of the protonophore mode of action of niclosamide. Niclosamide readily passes through biological membranes due to its lipophilic nature, as indicated by log P = 4.48 at pH 7.0 <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002976#ppat.1002976-Anonymous1" target="_blank">[33]</a>. Niclosamide (pKa of 5.6) is protonated in the acidic compartment of endosomes, and thereby increases its lipophilicity (log P = 5.63 at pH 5.7). This may enhance its partitioning into the lipid bilayer. In the pH-neutral cytosol a proton dissociates and the compound can interact again with membranes to repeat the cycle. Note that the location of the proposed negative charge on niclosamide is not known.</p

Niclosamide neutralizes acidic endosomal pH and alters the distribution of endosomes.

<p>A). Ratiometric live cell imaging of acridine orange (AO) green and red fluorescence. Nuclei were stained with Hoechst. B). The mean and SEM values of lysotracker fluorescence from single cell measurements are plotted against niclosamide (µM) and BafA1 (nM) (n = 4) with an overview of lysotracker fluorescence from a 96-well plate. C). Low extracellular pH bypasses niclosamide's antiviral effect. Mean and SEM values of dsRNA-positive cells (n = 2). D). Influence of niclosamide on the distribution of EEA1 (red) or LAMP1 (green) positive endosomes observed in single section confocal micrographs where nuclei (blue) were stained with DAPI and filamentous actin (grey) with phalloidine. E). Quantification of the perinuclear intensity of EEA1 and LAMP1 positive endosomes of cells from automated microscopy and single cell analyses relative to wild type levels (0) with means and SEM (n = 8). F). Electron micrograph of a negatively stained cow brain CCV preparation. G). Percent normalized fluorescence of acridine orange (AO) (excitation 492 nm, emission 540 nm) of control and inhibitor-treated CCV. The 100% signal is equivalent to the DMSO control treated vesicles.</p

Niclosamide inhibits virus entry post the 19°C compartment.

<p>A). Time course of niclosamide (12.5 µM) addition and assessment of HRV2 infection of HeLa cells, including DAPI staining for nuclei. B). Quantification of HRV2 and CVB3 infections from panel A with means of infection values including SEM (n = 4). C). Impact of a drug washout on niclosamide efficacy against HRV1A, 16 and CVB3. Cells were pre-incubated with 10 µM of compound for 30 min and either washed three times with PBS or drug. Mean values and SEM of n = 4 are shown relative to DMSO treated control cells. D). Efficacy of BafA1 (50 nM), pleconaril (0.5 µg/ml) and niclosamide (5 µM) added to cells, which had been inoculated with HRV16, 1A or CVB3 for 1, 2 or 3 h at 19°C. Mean infection values and SEM of n = 3 are shown relative to DMSO controls.</p