Lipopolysaccharides with Acylation Defects Potentiate TLR4 Signaling and Shape T Cell Responses

Lipopolysaccharides or endotoxins are components of Gram-negative enterobacteria that cause septic shock in mammals. However, a LPS carrying hexa-acyl lipid A moieties is highly endotoxic compared to a tetra-acyl LPS and the latter has been considered as an antagonist of hexa-acyl LPS-mediated TLR4 signaling. We investigated the relationship between the structure and the function of bacterial LPS in the context of human and mouse dendritic cell activation. Strikingly, LPS with acylation defects were capable of triggering a strong and early TLR4-dependent DC activation, which in turn led to the activation of the proteasome machinery dampening the pro-inflammatory cytokine secretion. Upon activation with tetra-acyl LPS both mouse and human dendritic cells triggered CD4⁺ T and CD8⁺ T cell responses and, importantly, human myeloid dendritic cells favored the induction of regulatory T cells. Altogether, our data suggest that LPS acylation controlled by pathogenic bacteria might be an important strategy to subvert adaptive immunity.     

Risk Factors for Acute Kidney Injury in Severe Rhabdomyolysis

Background

Acute kidney injury (AKI) is a life-threatening complication of severe rhabdomyolysis. This study was conducted to assess risk factors for AKI and to develop a risk score for early prediction.

Methods

Retrospective observational cohort study with a 9-year follow-up, carried out in an acute-care teaching-affiliated hospital. A total of 126 patients with severe rhabdomyolysis defined as serum creatine kinase (CK) > 5,000 IU/L fulfilled the inclusion criteria. Univariate and logistic regression analyses were performed to determine risk factors for AKI. Based on the values obtained for each variable, a risk score and prognostic probabilities were estimated to establish the risk for developing AKI.

Results

The incidence of AKI was 58%. Death during hospitalization was significantly higher among patients with AKI, compared to patients without AKI (19.2% vs 3.6%, p = 0.008). The following variables were independently associated with AKI: peak CK (odds ratio [OR] 4.9, 95%CI 1.4-16.8), hypoalbuminemia (< 33 mg/dL, [OR 5.1, 95%CI 1.4-17-7]), metabolic acidosis (OR 5.3, 95%CI 1.4-20.3), and decreased prothrombin time (OR 4.4, 95% CI 1.3-14.5). A risk score for AKI was calculated for each patient, with an OR of 1.72 (95%CI 1.45-2.04). The discrimination value of the predictive model was established by means of a ROC curve, with the area under the curve of 0.871 (p<0.001).

Conclusions

The identification of independent factors associated with AKI and a risk score for early prediction of this complication in patients with severe rhabdomyolysis may be useful in clinical practice, particularly to implement early preventive measures.     

Effects of Posidonia Oceanica Beach-Cast on Germination,Growth and Nutrient Uptake of Coastal Dune Plants

Seagrass meadows play an important role in marine ecosystems. A part of seagrass production is also exported to adjacent coastal terrestrial systems, possibly influencing their functioning. In this work we experimentally analyzed the effect of Posidonia oceanica beach-cast on plant germination, growth, and nutrient uptake of two plant species (Cakile maritima and Elymus farctus) that grow on upper beaches and fore dunes along the Mediterranean coasts. We compared plants growing in simple sand (control) with those growing in a substrate enriched with P. oceanica wrack (treatment) in laboratory. P. oceanica wrack doubled the N substrate pool and kept the substrate humid. Plants growing in the treated substrate grew faster, were twice as large as those growing in the control substrate, while tissues were enriched in N and P (Cakile by the 1.3 fold in N and 2.5 fold in P; Elymus by 1.5 fold in N and 2 fold in P). Our results suggest a positive effect of seagrass litter for the enhancing of dune species, highlighting its role for the conservation of coastal dune ecosystems.     

Comparative transcript profiling of a peach and its nectarine mutant at harvest reveals differences in gene expression related to storability

Gene expression at harvest was compared for two stone fruit cultivars, a peach and its near-isogenic nectarine mutant, using two microarray platforms, μPEACH1.0 and ChillPeach. Together, both platforms covered over 6,000 genes out of which 417 were differentially expressed between the fruits of the two cultivars at a p value of 0.05. A total of 47 genes in nectarine and 60 genes in peach were at least twofold higher relative to each other. Nectarine had much better storage characteristics than peach and could be stored for over 5 weeks at 5 °C without storage disorders. In an attempt to determine whether gene expression at harvest could give an indication of storage potential, the expression analysis of the two cultivars was compared to that of two genotypes with different sensitivities to chilling injury. Principal component analysis of gene expression results across four fruit types differing in chilling sensitivity resulted in 41 genes whose expression levels separated the fruits according to sensitivity to storage disorders, suggesting that the genes have a role in cold response adaptation.     

Differential Expression of Apoptosis Related Genes in Selected Strains of Aedes aegypti with Different Susceptibilities to Dengue Virus

Aedes aegypti is the principal vector of Dengue viruses worldwide. We identified field collected insects with differential susceptibility to Dengue-2 virus (DENv-2) and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. Previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. To identify potential molecular mechanisms associated with DENv susceptibility, we evaluated the differential expression of Caspase-16, Aedronc, Aedredd, Inhibitor of apoptosis (AeIAP1) and one member of the RNAi pathway, Argonaute-2 in the midguts and fat body tissues of the selected strains at specific times post blood feeding or infection with DENv-2. In the refractory strain there was significantly increased expression of caspases in midgut and fatbody tissues in the presence of DENv-2, compared to exposure to blood alone, and significantly higher caspase expression in the refractory strain compared with the susceptible strain at timepoints when DENv was establishing in these tissues. We used RNAi to knockdown gene expression; knockdown of AeIAP1 was lethal to the insects. In the refractory strain, knockdown of the pro-apoptotic gene Aedronc increased the susceptibility of refractory insects to DENv-2 from 53% to 78% suggesting a contributing role of this gene in the innate immune response of the refractory strain.     

Scavengers on the Move: Behavioural Changes in Foraging Search Patterns during the Annual Cycle

Background

Optimal foraging theory predicts that animals will tend to maximize foraging success by optimizing search strategies. However, how organisms detect sparsely distributed food resources remains an open question. When targets are sparse and unpredictably distributed, a Lévy strategy should maximize foraging success. By contrast, when resources are abundant and regularly distributed, simple Brownian random movement should be sufficient. Although very different groups of organisms exhibit Lévy motion, the shift from a Lévy to a Brownian search strategy has been suggested to depend on internal and external factors such as sex, prey density, or environmental context. However, animal response at the individual level has received little attention.

Methodology/Principal Findings

We used GPS satellite-telemetry data of Egyptian vultures Neophron percnopterus to examine movement patterns at the individual level during consecutive years, with particular interest in the variations in foraging search patterns during the different periods of the annual cycle (i.e. breeding vs. non-breeding). Our results show that vultures followed a Brownian search strategy in their wintering sojourn in Africa, whereas they exhibited a more complex foraging search pattern at breeding grounds in Europe, including Lévy motion. Interestingly, our results showed that individuals shifted between search strategies within the same period of the annual cycle in successive years.

Conclusions/Significance

Results could be primarily explained by the different environmental conditions in which foraging activities occur. However, the high degree of behavioural flexibility exhibited during the breeding period in contrast to the non-breeding period is challenging, suggesting that not only environmental conditions explain individuals'' behaviour but also individuals'' cognitive abilities (e.g., memory effects) could play an important role. Our results support the growing awareness about the role of behavioural flexibility at the individual level, adding new empirical evidence about how animals in general, and particularly scavengers, solve the problem of efficiently finding food resources.     

Efficacy and Safety of A Liposome-Based Vaccine against Protein Tau,Assessed in Tau.P301L Mice That Model Tauopathy

Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimer''s disease. The unmet need of effective therapy for Alzheimer''s disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404. We demonstrate that the liposome-based vaccine elicited, rapidly and robustly, specific antisera in wild-type mice and in Tau.P301L mice. Long-term vaccination proved to be safe, because it improved the clinical condition and reduced indices of tauopathy in the brain of the Tau.P301L mice, while no signs of neuro-inflammation or other adverse neurological effects were observed. The data corroborate the hypothesis that liposomes carrying phosphorylated peptides of protein Tau have considerable potential as safe and effective treatment against tauopathies, including Alzheimer''s disease.     

Reaching the Unreachable: Providing STI Control Services to Female Sex Workers via Mobile Team Outreach

Background

As part of a community-randomized trial of a multicomponent intervention to prevent sexually transmitted infections, we created Mobile Teams (MTs) in ten intervention cities across Peru to improve outreach to female sex workers (FSW) for strengthened STI prevention services.

Methods

Throughout 20 two-month cycles, MTs provided counseling; condoms; screening and specific treatment for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), and vaginal Trichomonas vaginalis (TV) infections; and periodic presumptive metronidazole treatment for vaginal infections.

Results

MTs had 48,207 separate encounters with 24,814 FSW; numbers of sex work venues and of FSW reached increased steadily over several cycles. Approximately 50% of FSW reached per cycle were new. Reported condom use with last client increased from 73% to 93%. Presumptive metronidazole treatment was accepted 83% of times offered. Over 38 months, CT prevalence declined from 15·4% to 8·2%, and TV prevalence from 7·3% to 2·6%. Among participants in ≥9 cycles, CT prevalence decreased from 12·9% to 6·0% (p <0·001); TV from 4·6% to 1·5% (p <0·001); and NG from 0·8% to 0·4% (p =0·07).

Conclusions

Mobile outreach to FSW reached many FSW not utilizing government clinics. Self-reported condom use substantially increased; CT and TV prevalences declined significantly. The community-randomized trial, reported separately, demonstrated significantly greater reductions in composite prevalence of CT, NG, TV, or high-titer syphilis serology in FSW in these ten intervention cities than in ten matched control cities.