Opposite Effects of Low and High Doses of Aβ42 on Electrical Network and Neuronal Excitability in the Rat Prefrontal Cortex

Changes in neuronal synchronization have been found in patients and animal models of Alzheimer''s disease (AD). Synchronized behaviors within neuronal networks are important to such complex cognitive processes as working memory. The mechanisms behind these changes are not understood but may involve the action of soluble β-amyloid (Aβ) on electrical networks. In order to determine if Aβ can induce changes in neuronal synchronization, the activities of pyramidal neurons were recorded in rat prefrontal cortical (PFC) slices under calcium-free conditions using multi-neuron patch clamp technique. Electrical network activities and synchronization among neurons were significantly inhibited by low dose Aβ42 (1 nM) and initially by high dose Aβ42 (500 nM). However, prolonged application of high dose Aβ42 resulted in network activation and tonic firing. Underlying these observations, we discovered that prolonged application of low and high doses of Aβ42 induced opposite changes in action potential (AP)-threshold and after-hyperpolarization (AHP) of neurons. Accordingly, low dose Aβ42 significantly increased the AP-threshold and deepened the AHP, making neurons less excitable. In contrast, high dose Aβ42 significantly reduced the AP-threshold and shallowed the AHP, making neurons more excitable. These results support a model that low dose Aβ42 released into the interstitium has a physiologic feedback role to dampen electrical network activity by reducing neuronal excitability. Higher concentrations of Aβ42 over time promote supra-synchronization between individual neurons by increasing their excitability. The latter may disrupt frontal-based cognitive processing and in some cases lead to epileptiform discharges.     

Comparative and phylogenomic analyses of cinnamoyl-CoA reductase and cinnamoyl-CoA-reductase-like gene family in land plants

The biosynthesis of monolignols, the main components of lignin, involves many intermediates and enzymes. The cinnamoyl-CoA reductase (CCR) enzyme catalyzes the conversion of cinnamoyl-CoAs to cinnamaldehydes, i.e. the first specific step in lignin synthesis. The CCR and CCR-like gene family was studied partially in several plant species. This is a comprehensive study of the CCR and CCR-like gene family including genome organization, gene structure, phylogeny across land plant species, and, expression profiling in Populus. Analysis of amino acid motifs enabled the identification of sequence variations in the CCR catalytic site and annotates CCR and CCR-like genes. CCR and CCR-like genes were distributed in three major phylogenetic classes of which one includes the bona fide CCR genes. The other two classes include CCR and CCR-like, of which several genes present a high similarity to cinnamyl alcohol dehydrogenase, or dihydroflavonol reductase (DFR) genes. All CCR, CCR-like, and DFR classes were deeply rooted in the phylogeny of land plants suggesting that their evolution preceded the evolution of lycophytes. Over two thirds of CCR and CCR-like Populus genes were physically distributed on duplicated regions. This suggests that these duplication/retention processes contributed significantly to the size of the CCR and CCR-like gene family. The Populus CCR and CCR-like genes showed six expression patterns in the tissues studied with a preferential expression of PoptrCCR12 in xylem. The other genes present divergent expression profiles with some preferentially expressed in leaves, bark, or both. Several CCR and CCR-like genes were induced or repressed under various abiotic stresses suggesting that their duplication was followed by the evolution of divergent expression profiles and divergence of functions.     

IL-28B is a Key Regulator of B- and T-Cell Vaccine Responses against Influenza

Influenza is a major cause of morbidity and mortality in immunosuppressed persons, and vaccination often confers insufficient protection. IL-28B, a member of the interferon (IFN)-λ family, has variable expression due to single nucleotide polymorphisms (SNPs). While type-I IFNs are well known to modulate adaptive immunity, the impact of IL-28B on B- and T-cell vaccine responses is unclear. Here we demonstrate that the presence of the IL-28B TG/GG genotype (rs8099917, minor-allele) was associated with increased seroconversion following influenza vaccination (OR 1.99 p = 0.038). Also, influenza A (H1N1)-stimulated T- and B-cells from minor-allele carriers showed increased IL-4 production (4-fold) and HLA-DR expression, respectively. In vitro, recombinant IL-28B increased Th1-cytokines (e.g. IFN-γ), and suppressed Th2-cytokines (e.g. IL-4, IL-5, and IL-13), H1N1-stimulated B-cell proliferation (reduced 70%), and IgG-production (reduced>70%). Since IL-28B inhibited B-cell responses, we designed antagonistic peptides to block the IL-28 receptor α-subunit (IL28RA). In vitro, these peptides significantly suppressed binding of IFN-λs to IL28RA, increased H1N1-stimulated B-cell activation and IgG-production in samples from healthy volunteers (2-fold) and from transplant patients previously unresponsive to vaccination (1.4-fold). Together, these findings identify IL-28B as a key regulator of the Th1/Th2 balance during influenza vaccination. Blockade of IL28RA offers a novel strategy to augment vaccine responses.     

Vancomycin-Eluting Niosomes: A New Approach to the Inhibition of Staphylococcal Biofilm on Abiotic Surfaces

A new vancomycin (VCM)-eluting mixed bilayer niosome formulation was evaluated for the control of staphylococcal colonization and biofilm formation on abiotic surfaces, a niosome application not explored to date. Cosurfactant niosomes were prepared using a Span 60/Tween 40/cholesterol blend (1: 1: 2). Tween 40, a polyethoxylated amphiphile, was included to enhance VCM entrapment and confer niosomal surface properties precluding bacterial adhesion. VCM-eluting niosomes showed good quality attributes including relatively high entrapment efficiency (～50%), association of Tween 40 with vesicles in a constant proportion (～87%), biphasic release profile suitable for inhibiting early bacterial colonization, and long-term stability at 4°C for a 12-month study period. Niosomes significantly enhanced VCM activity against planktonic bacteria of nine staphylococcal strains. Using microtiter plates as abiotic surface, VCM-eluting niosomes proved superior to VCM in inhibiting biofilm formation, eradicating surface-borne biofilms, inhibiting biofilm growth, and interfering with biofilm induction by VCM subminimal inhibitory concentrations. Data suggest dual functionality of cosurfactant VCM-eluting niosomes as passive colonization inhibiting barrier and active antimicrobial-controlled delivery system, two functions recognized in infection control of abiotic surfaces and medical devices.     

Growth of Listeria monocytogenes and Yersinia enterocolitica on Cooked Modified-Atmosphere-Packaged Poultry in the Presence and Absence of a Naturally Occurring Microbiota

Cooked poultry cuts were inoculated with five-strain composite mixtures of either Listeria monocytogenes or Yersinia enterocolitica (1,000 CFU/150-g piece), packaged in 44:56 CO₂-N₂, and stored at 3.5, 6.5, or 10°C for up to 5 weeks. Both L. monocytogenes and Y. enterocolitica grew under all test conditions. The presence of a naturally occurring microbiota did not influence the growth of either pathogen. Addition of lactate with the shelf life extender ALTA 2341 lengthened the lag phases of L. monocytogenes and Y. enterocolitica but did not prevent their growth.     

The genetic basis of spectral reflectance indices in drought-stressed wheat

Drought imposes a major constraint over the productivity of wheat, particularly in arid and semi-arid production zones. Here, the genetic basis of spectral reflectance indices was investigated in drought-stressed wheat by comparing, under two contrasting moisture regimes, the performance of an F₆ recombinant inbred line (RIL) population bred from a cross between the drought tolerant cultivar Pavon76 and the sensitive cultivar Yecora Rojo. The parents and RILs were genotyped with respect to both a set of microsatellite (SSR) loci and a number of known drought-responsive genes. In all, 28 quantitative trait loci (QTL) controlling dry weight per plant, water content of the above-ground biomass, leaf water potential, canopy temperature, and spectral reflectance indices traits were identified. The loci were distributed over 11 chromosomes, belonging to each of the three wheat sub-genomes. There were important location-flanking markers Barc109 and Barac4 on chromosome 5B relating to dry weight per plant accumulation under the limited irrigation regime. The same region-harbored QTL associated with leaf water potential, canopy temperature, and ratio index under the limited irrigation regime. Linkage between the known drought-responsive genes and aspects of the drought response was established. Some of QTL were of substantial enough effect for their linked markers to be likely usable for the marker-assisted breeding of drought tolerance in wheat.     

Computational Fluid Dynamic Simulations of Maternal Circulation: Wall Shear Stress in the Human Placenta and Its Biological Implications

Introduction

In the human placenta the maternal blood circulates in the intervillous space (IVS). The syncytiotrophoblast (STB) is in direct contact with maternal blood. The wall shear stress (WSS) exerted by the maternal blood flow on the STB has not been evaluated. Our objective was to determine the physiological WSS exerted on the surface of the STB during the third trimester of pregnancy.

Material and Methods

To gain insight into the shear stress levels that the STB is expected to experience in vivo, we have formulated three different computational models of varying levels of complexity that reflect different physical representations of the IVS. Computations of the flow fields in all models were performed using the CFD module of the finite element code COMSOL Multiphysics 4.4. The mean velocity of maternal blood in the IVS during the third trimester was measured in vivo with dynamic MRI (0.94±0.14 mm.s^-1). To investigate if the in silico results are consistent with physiological observations, we studied the cytoadhesion of human parasitized (Plasmodium falciparum) erythrocytes to primary human STB cultures, in flow conditions with different WSS values.

Results

The WSS applied to the STB is highly heterogeneous in the IVS. The estimated average values are relatively low (0.5±0.2 to 2.3±1.1 dyn.cm^-2). The increase of WSS from 0.15 to 5 dyn.cm^-2 was associated with a significant decrease of infected erythrocyte cytoadhesion. No cytoadhesion of infected erythrocytes was observed above 5 dyn.cm^-2 applied for one hour.

Conclusion

Our study provides for the first time a WSS estimation in the maternal placental circulation. In spite of high maternal blood flow rates, the average WSS applied at the surface of the chorionic villi is low (<5 dyn.cm^-2). These results provide the basis for future physiologically-relevant in vitro studies of the biological effects of WSS on the STB.     

Humoral mechanisms in the regulation of work hyperthermia

Thermal reactions were investigated in rabbits: blood plasma donors running on treadmill to exhaustion and resting blood plasma recipients. Blood plasma was infused in the ear's vein and in the third brain ventricle cavity. Small elevation of body cork temperature (0.3-0.4 degree C) with the latent period 40-50 min was found on plasma infusion in the ear's vein of recipient. Plasma perfusion through the third brain ventricle of the recipient caused two peaks of nearly the same amplitude (0.8-1.0 degrees C) in body core temperature. The second peak, which was registered in 12-15 min after the perfusion began, was induced, as the authors suggest, by the accumulation of "work factor" of thermoregulation in donor's plasma during muscular work. Humoral regulation of working hyperthermia is discussed.     

Zinc-phosphorus relationship in the nutrition of corn plants (Zea mays L.) grown on some calcareous soils

Summary Positive relationships were observed between Zn and P in the studied calcareous soils and in the corn plants grown thereon. The high content of carbonates in these soils affected greatly the levels of extractable Zn and the Zn–P relationships. In the pot experiment, application of P increased the Zn content of the corn plants and application of Zn increased that of P.