Francisella tularensis LVS-induced Interleukin-12 p40 cytokine production mediates dendritic cell migration through IL-12 Receptor β1

Three cytokines use the IL-12p40 cytokine subunit namely: IL-12p70 (IL-12-comprised of IL-12p40 and IL-12p35), IL-23 (comprised of the IL-12p40 and IL-23p19 subunits) and homodimeric IL-12p40 (IL-12(p40)(2)). Following activation, immature dendritic cells (DCs) upregulate the chemokine receptor Chemokine-C-Receptor 7 (CCR7), and migrate in response to homeostatic chemokines such as chemokine (C-C motif) ligand 19 (CCL19). Induction of the cytokine IL-12p40 in response to pathogen-exposure, likely in its homodimeric form, is one of the primary events that mediates migration of DCs in response to CCL19. Here we show that following exposure to Francisella tularensis Live Vaccine Strain (LVS), DCs produce IL-12p40 and promote the migration of DCs to the chemokine CCL19 in an IL-12Rβ1- and IL-12p(40)(2)-dependent manner. Induction of IL-12p40 and resulting chemokine responsiveness in DCs is TLR2-dependent and coincides with the uptake of F. tularensis LVS and activation of DCs. Importantly, we show that IL-12Rβ1 signaling is required for DC migration from the lung to the draining lymph node following F. tularensis LVS exposure and coincides with accumulation of IL-12p40 expressing DCs in the draining lymph nodes. Together, these findings illustrate that IL-12p40 is induced rapidly in response to F. tularensis LVS and is required for DC migration through an IL-12Rβ1-IL-12(p40)(2) dependent mechanism.     

Investigation of parent-of-origin effects induced by fenofibrate treatment on triglycerides levels

Background

Genome-wide association studies performed on triglycerides (TGs) have not accounted for epigenetic mechanisms that may partially explain trait heritability.

Results

Parent-of-origin (POO) effect association analyses using an agnostic approach or a candidate approach were performed for pretreatment TG levels, posttreatment TG levels, and pre- and posttreatment TG-level differences in the real GAW20 family data set. We detected 22 genetic variants with suggestive POO effects with at least 1 phenotype (P ≤ 10^− 5). We evaluated the association of these 22 significant genetic variants showing POO effects with close DNA methylation probes associated with TGs. A total of 18 DNA methylation probes located in the vicinity of the 22 SNPs were associated with at least 1 phenotype and 6 SNP-probe pairs were associated with DNA methylation probes at the nominal level of P < 0.05, among which 1 pair presented evidence of POO effect. Our analyses identified a paternal effect of SNP rs301621 on the difference between pre- and posttreatment TG levels (P = 1.2 × 10^− 5). This same SNP showed evidence for a maternal effect on methylation levels of a nearby probe (cg10206250; P = 0.01). Using a causal inference test we established that the observed POO effect of rs301621 was not mediated by DNA methylation at cg10206250.

Conclusions

We performed POO effect association analyses of SNPs with TGs, as well as association analyses of SNPs with DNA methylation probes. These analyses, which were followed by a causal inference test, established that the paternal effect at the SNP rs301621 is induced by treatment and is not mediated by methylation level at cg10206250.

     

Species differences and mechanism of action of A<Subscript>3</Subscript> adenosine receptor allosteric modulators

Activity of the A₃ adenosine receptor (AR) allosteric modulators LUF6000 (2-cyclohexyl-N-(3,4-dichlorophenyl)-1H-imidazo [4,5-c]quinolin-4-amine) and LUF6096 (N-{2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarbox-amide) was compared at four A₃AR species homologs used in preclinical drug development. In guanosine 5′-[γ-[³⁵S]thio]triphosphate ([³⁵S]GTPγS) binding assays with cell membranes isolated from human embryonic kidney cells stably expressing recombinant A₃ARs, both modulators substantially enhanced agonist efficacy at human, dog, and rabbit A₃ARs but provided only weak activity at mouse A₃ARs. For human, dog, and rabbit, both modulators increased the maximal efficacy of the A₃AR agonist 2-chloro-N ⁶-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide as well as adenosine > 2-fold, while slightly reducing potency in human and dog. Based on results from N ⁶-(4-amino-3-[¹²⁵I]iodobenzyl)adenosine-5′-N-methylcarboxamide ([¹²⁵I]I-AB-MECA) binding assays, we hypothesize that potency reduction is explained by an allosterically induced slowing in orthosteric ligand binding kinetics that reduces the rate of formation of ligand-receptor complexes. Mutation of four amino acid residues of the human A₃AR to the murine sequence identified the extracellular loop 1 (EL1) region as being important in selectively controlling the allosteric actions of LUF6096 on [¹²⁵I]I-AB-MECA binding kinetics. Homology modeling suggested interaction between species-variable EL1 and agonist-contacting EL2. These results indicate that A₃AR allostery is species-dependent and provide mechanistic insights into this therapeutically promising class of agents.     

Prospects for improved off-crop habitat management for pollen beetle control in oilseed rape

There is an urgent need to develop sustainable and environmentally benign integrated pest management (IPM) strategies for arable crops. The enhancement and manipulation of naturally occurring populations of the natural enemies of crop pests through habitat management for ‘conservation biological control’, as well as habitat management to manipulate populations of the pests themselves, have the potential to become major components of successful IPM strategies. We review the studies that have contributed to our current understanding of how the crop margin, local landscape, and regional landscape can influence pollen beetle Brassicogethes aeneus (syn. Meligethes aeneus) (Coleoptera: Nitidulidae) abundance and damage to oilseed rape crops (Brassica napus), and the efficacy of their natural enemies. We also discuss how habitat management across these multiple scales may improve pollen beetle control, reducing the need for insecticide use and contributing towards sustainable production of this important crop which is grown on increasing areas for both food and fuel.     

Sleep quality,sleepiness and the influence of workplace breaks: A cross-sectional survey of health-care workers in two US hospitals

ABSTRACT

This study assessed sleep quality, sleepiness and use of workplace break opportunities in 1285 health-care workers via an online questionnaire. Two hospitals were surveyed – one with and one without a fatigue mitigation policy. Across all respondents, 68.9% reported generally taking breaks of at least 30 min and 21.7% had access to a quiet place to rest, with no significant differences between hospitals. The presence of a fatigue mitigation policy was not associated with reduced sleepiness. However, accounting for hospital and shift characteristics, employees with access to a quiet place to rest while on break had significantly lower self-reported sleepiness scores.     

Benthic primary production and nitrogen cycling in Spartina alterniflora marshes: effect of restoration after acute dieback

The sudden and massive Spartina alterniflora dieback at the turn of the millennium generated numerous unanswered questions regarding its mechanistic causes and consequences. This study, conducted during 2007–2008, aimed to elucidate mechanisms of recovery and determine whether recovery was accelerated by replanting efforts. The onset of a severe drought during the summer of 2007, however, provided a potential glimpse into the mechanisms driving dieback events. Study sites were established in two of the hardest hit states, Georgia and Louisiana. Each site had a replicated block design consisting of the following four treatments: reference, dieback, dieback with low density replanting (90 cm spacing), and dieback with high density replanting (30 cm spacing). To assess biogeochemical cycling and ecosystem functioning, we quantified rates of nitrogen fixation, potential nitrification, potential denitrification, and benthic production biannually. All measured process rates decreased following the drought year of 2007. Nitrogen fixation was positively correlated with benthic production rates in Louisiana, while denitrification was positively correlated with benthic production rates in Georgia and Louisiana. The lack of decreased benthic production during the 2007 drought could indicate that benthic microphytes cope with better with drought than plants, but may be outcompeted during non-drought years. Replanting efforts significantly increased ecosystem recovery in Louisiana and to a lesser extent in Georgia.     

Increasing Cognitive Load Reduces Interference from Masked Appetitive and Aversive but Not Neutral Stimuli

Interactions between cognition and emotion are important for survival, often occurring in the absence of awareness. These interactions have been proposed to involve competition between cognition and emotion for attentional resources. Emotional stimuli have been reported to impair performance on cognitive tasks of low, but not high, load if stimuli are consciously perceived. This study explored whether this load-dependent interference effect occurred in response to subliminal emotional stimuli. Masked emotional (appetitive and aversive), but not neutral, stimuli interfered with performance accuracy but not response time on a cognitive task (n-back) at low (1-back), but not high (2-back) load. These results show that a load-dependent interference effect applies to masked emotional stimuli and that the effect generalises across stimulus categories with high motivational value. This supports models of selective attention that propose that cognition and emotion compete for attentional resources. More specifically, interference from masked emotional stimuli at low load suggests that attention is biased towards salient stimuli, while dissipation of interference under high load involves top-down regulation of attention. Our data also indicate that top-down goal-directed regulation of attention occurs in the absence of awareness and does not require metacognitive monitoring or evaluation of bias over behaviour, i.e., some degree of self-regulation occurs at a non-conscious level.     

Gender-Specific Effects of Depression and Suicidal Ideation in Prosocial Behaviors

Background

Prosocial behaviors are essential to the ability to relate to others. Women typically display greater prosocial behavior than men. The impact of depression on prosocial behaviors and how gender interacts with those effects are not fully understood. We explored the role of gender in the potential effects of depression on prosocial behavior.

Methods

We examined prosocial behaviors using a modified version of the Trust Game in a clinical population and community controls. Study participants were characterized on the severity of depression and anxiety, presence of suicidal ideation, history of childhood trauma, recent stressful life events, and impulsivity. We correlated behavioral outcomes with gender and clinical variables using analysis of variance and multiple regression analysis.

Results

The 89 participants comprised four study groups: depressed women, depressed men, healthy women and healthy men (n = 16–36). Depressed men exhibited reciprocity more frequently than healthy men. Depression induced an inversion of the gender-specific pattern of self-centered behavior. Suicidal ideation was associated with increased reciprocity behavior in both genders, and enhancement of the effect of depression on gender-specific self-centered behavior.

Conclusions

Depression, particularly suicidal ideation, is associated with reversal of gender-specific patterns of prosocial behavior, suggesting abnormalities in sexual hormones regulation. This explanation is supported by known abnormalities in the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axes found in depression.     

Developmental variation in copper,zinc and metallothionein mRNA in brindled mutant and nutritionally copper deficient mice

The concentrations of copper, zinc and metallothionein-I (MT-I) mRNA were determined in the liver, kidney and brain of the brindled mutant mouse from birth until the time of death. Despite accumulation of copper in the kidney of the mutant, MT-I mRNA concentrations were normal. There was no difference between the MT-I mRNA in the brain of mutant and normal in the first 10 days of life, but after day 10 metallothionein mRNA levels were increased in the mutant. The concentration of copper was very low in the liver of the mutant, and on day 6 after birth the metallothionein mRNA was also reduced by about 50%. This reduction was not seen in copper-deficient 6-day-old pups, despite very low hepatic copper levels. This suggests that the lower hepatic MT-I mRNA in the day 6 brindled mouse was not simply due to the reduction in hepatic copper and also that hepatic copper is not regulating metallothionein gene expression the liver of neonatal mice. After day 12 hepatic MT-I mRNA levels were elevated in mutant and in copper deficient mice, both of which die at 14 to 16 days. These increases and the increase in brain MT-I mRNA in older mutant mice are likely to be caused by stress. Overall the results support the conclusions that the brindled mutation does not cause a constitutive activation of the metallothionein genes, and that the differences in metallothionein mRNA between mutant and normal are most probably secondary consequences of the mutation.