Context-dependent encoding of fear and extinction memories in a large-scale network model of the basal amygdala

The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories.     

p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects

Suppression of macroautophagy, due to mutations or through processes linked to aging, results in the accumulation of cytoplasmic substrates that are normally eliminated by the pathway. This is a significant problem in long-lived cells like neurons, where pathway defects can result in the accumulation of aggregates containing ubiquitinated proteins. The p62/Ref(2)P family of proteins is involved in the autophagic clearance of cytoplasmic protein bodies or sequestosomes. These unique structures are closely associated with protein inclusions containing ubiquitin as well as key components of the autophagy pathway. In this study we show that detergent fractionation followed by western blot analysis of insoluble ubiquitinated proteins (IUP), mammalian p62 and its Drosophila homologue, Ref(2)P can be used to quantitatively assess the activity level of aggregate clearance (aggrephagy) in complex tissues. Using this technique we show that genetic or age-dependent changes that modify the long-term enhancement or suppression of aggrephagy can be identified. Moreover, using the Drosophila model system this method can be used to establish autophagy-dependent protein clearance profiles that are occurring under a wide range of physiological conditions including developmental, fasting and altered metabolic pathways. This technique can also be used to examine proteopathies that are associated with human disorders such as frontotemporal dementia, Huntington and Alzheimer disease. Our findings indicate that measuring IUP profiles together with an assessment of p62/Ref(2)P proteins can be used as a screening or diagnostic tool to characterize genetic and age-dependent factors that alter the long-term function of autophagy and the clearance of protein aggregates occurring within complex tissues and cells.     

Neuromuscular efficiency during sit to stand movement in women with knee osteoarthritis

The purpose of this study was to investigate the neuromuscular efficiency of women with knee osteoarthritis (OA) when performing a sit-to-stand movement and during maximum strength efforts. Twelve women with unilateral knee OA (age 60.33 ± 6.66 years, height 1.61 ± 0.05 m, mass 77.08 ± 9.2 kg) and 11 controls (age 56.54 ± 5.46 years, height 1.64 ± 0.05 m, mass 77.36 ± 13.34 kg) participated in this study. Subjects performed a sit-to-stand movement from a chair while position of center of pressure and knee angular speed were recorded. Furthermore, maximal isokinetic knee extension and flexion strength at 60°/s, 120°/s and 150°/s was measured. Surface, electromyography (EMG) from the biceps femoris (BF), vastus lateralis (VL) and vastus medialis (VM) was recorded during all tests. Analysis of variance (ANOVA) showed that during the sit-to-stand OA group demonstrated significantly lower knee angular speed (44.49 ± 9.61°/s vs. 71.68 ± 19.86°/s), a more posterior position of the center of pressure (39.20 ± 7.02% vs. 41.95 ± 2.49%) and a higher antagonist BF activation (57.13 ± 20.55% vs. 32.01 ± 19.5%) compared with controls (p < 0.05). Further, women with knee OA demonstrated a lower Moment-to-EMG ratio than controls in extension and eccentric flexion at 60°/s and 150°/s, while the opposite was found for concentric flexion at 60°/s (p < 0.05). Among other factors, the slower performance of the sit-to-stand movement in women with OA is due to a less efficient use of the knee extensor muscles (less force per unit of EMG) and, perhaps, a higher BF antagonist co-activation. This may lead subjects with OA to adopt a different movement strategy compared with controls.     

Study of changes in physicochemical and microbiological characteristics of shrimps (Melicertus kerathurus) stored under modified atmosphere packaging

Fresh minimally processed shrimps were stored under modified atmosphere packaging (60% CO₂:40% N₂ for MAP A and 92.9% N₂:5.1% CO₂:2% O₂ for MAP B) for 5 days at 3 °C. Total mesophiles, H₂S forming bacteria, Pseudomonas spp., Brochothrix thermosphacta, firmness, color and sensory parameters were investigated throughout the whole time of the experiment. During storage period samples stored under MAP B managed to retain firmness values close to the initial values. All microbial populations growth was suppressed by the presence of MAP A. Samples stored under MAP B managed to maintain their firmness values close to the initial ones while MAP A samples were significantly less firm (p < 0.05).     

Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21

Fibroblast growth factor-21 (FGF21) is a pleiotropic protein involved in glucose, lipid metabolism and energy homeostasis, with main tissues of expression being the liver and adipose tissue. Brown adipose tissue (BAT) is responsible for cold-induced thermogenesis in rodents. The role of FGF21 in BAT biology has not been investigated. In the present study, wild-type C57BL/6J mice as well as a brown adipocyte cell line were used to explore the potential role of cold exposure and β3-adrenergic stimulation in the expression of FGF21 in BAT. Our results demonstrate that short-term exposure to cold, as well as β3-adrenergic stimulation, causes a significant induction of FGF21 mRNA levels in BAT, without a concomitant increase in FGF21 plasma levels. This finding opens new routes for the potential use of pharmaceuticals that could induce FGF21 and, hence, activate BAT thermogenesis.     

Sex hormones in postmenopausal women receiving low-dose hormone therapy: the effect of BMI

The aim of our study was to evaluate the effect of BMI on the change in circulating sex hormone in postmenopausal women during 6 months of oral continuous combined low-dose hormone therapy (HT). Fifty postmenopausal women were allocated to receive daily one tablet containing combination of 17β-estradiol (1 mg)/norethindrone acetate (0.5 mg) for 6 months. Serum levels of follicle-stimulating hormone (FSH), estradiol, total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), free estrogen index (FEI), Δ4-androstendione (Δ4A), and dehydroepiandrosterone sulfate were assessed at baseline and at the end of 6 months. Mean absolute values and percent changes from baseline were compared between lean and overweight women. Mean FSH decreased and mean 17β-estradiol increased significantly in both groups (FSH lean: 82.3 ± 26.7 decreased to 45.0 ± 17.0 mIU/ml, P = 0.0001; FSH overweight: 85.5 ± 22.1 decreased to 52.3 ± 23.8 mIU/ml, P = 0.003; P between groups = 0.661; E2 lean: 23.24 ± 12.55 increased to 53.62 ± 28.29 pg/ml, P = 0.006; E2 overweight: 24.17 ± 10.88 increased to 68.36 ± 53.99 pg/ml, P = 0.0001; P between groups = 0.619). Lean individuals had statistically significant higher increments of FAI and specifically FEI compared to overweight (FEI lean; 0.14 ± 0.09 increased to 0.29 ± 0.14, P = 0.009; overweight 0.23 ± 0.18 increased to 0.52 ± 0.40, P = 0.126; P between groups = 0.034). Although BMI does not affect total 17β-estradiol changes, free sex steroid concentrations increase more steeply in lean compared to overweight women receiving oral low-dose HT.     

Impact of definitive therapy with beta-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia

Background

Bacteremia by Pseudomonas aeruginosa represents one severe infection. It is not clear whether beta-lactam monotherapy leads to similar rates of treatment success compared to combinations of beta-lactams with aminoglycosides or quinolones.

Methods

Retrospective cohort study from 3 tertiary hospitals (2 in Greece and 1 in Italy). Pseudomonas aeruginosa isolates were susceptible to a beta-lactam and an aminoglycoside or a quinolone. Patients received appropriate therapy for at least 48 hours. Primary outcome of interest was treatment success in patients with definitive beta-lactam combination therapy compared to monotherapy. Secondary outcomes were treatment success keeping the same empirical and definitive regimen, mortality, and toxicity.

Results

Out of 92 bacteremias there were 54 evaluable episodes for the primary outcome (20 received monotherapy). Treatment success was higher with combination therapy (85%) compared to beta-lactam monotherapy (65%), however not statistically significantly [Odds ratio (OR) 3.1; 95% Confidence Interval (CI) 0.69–14.7, p = 0.1]. Very long (>2 months) hospitalisation before bacteremia was the only factor independently associated with treatment success (OR 0.73; 95% CI 0.01–0.95, p = 0.046), however this result entailed few episodes. All-cause mortality did not differ significantly between combination therapy [6/31 (19%)] and monotherapy [8/19 (42%)], p = 0.11. Only Charlson comorbidity index was associated with excess mortality (p = 0.03).

Conclusion

Our study, in accordance with previous ones, indicates that the choice between monotherapy and combination therapy may not affect treatment success significantly. However, our study does not have statistical power to identify small or moderate differences. A large randomized controlled trial evaluating this issue is justified.     

Syncytins expression in cultured trophoblast cells according to differentiation status

Background  

Data of syncytin 1 and 2 env gene expression in human placenta and participation in the syncytialisation phenomena has been reported. However, there are not many studies on simultaneous changes in expression of both syncytins in culture. We sought evidence on the relative expression of syncytins and syncytin 1 receptors in trophoblast cell culture treated with a differentiation inducing factor (forskolin).