TLR signaling tailors innate immune responses in human microglia and astrocytes

The specific signals mediating the activation of microglia and astrocytes as a prelude to, or consequence of, CNS inflammation continue to be defined. We investigated TLRs as novel receptors mediating innate immune responses in human glial cells. We find that microglia express mRNA for TLRs 1-9, whereas astrocytes express robust TLR3, low-level TLR 1, 4, 5, and 9, and rare-to-undetectable TLR 2, 6, 7, 8, and 10 mRNA (quantitative real-time PCR). We focused on TLRs 3 and 4, which can signal through both the MyD88-dependent and -independent pathways, and on the MyD88-restricted TLR2. By flow cytometry, we established that microglia strongly express cell surface TLR2; TLR3 is expressed at higher levels intracellularly. Astrocytes express both cell surface and intracellular TLR3. All three TLRs trigger microglial activation upon ligation. TLR3 signaling induces the strongest proinflammatory polarizing response, characterized by secretion of high levels of IL-12, TNF-alpha, IL-6, CXCL-10, and IL-10, and the expression of IFN-beta. CXCL-10 and IL-10 secretion following TLR4 ligation are comparable to that of TLR3; however, other responses were lower or absent. TLR2-mediated responses are dominated by IL-6 and IL-10 secretion. Astrocytes respond to TLR3 ligation, producing IL-6, CXCL-10, and IFN-beta, implicating these cells as contributors to proinflammatory responses. Initial TLR-mediated glial activation also regulates consequent TLR expression; while TLR2 and TLR3 are subject to positive feedback, TLR4 is down-regulated in microglia. Astrocytes up-regulate all three TLRs following TLR3 ligation. Our data indicate that activation of innate immune responses in the CNS is not homogeneous but rather tailored according to cell type and environmental signal.     

New insights into the role of zinc in the respiratory epithelium

Over the past 30 years, many researchers have demonstrated the critical role of zinc (Zn), a group IIb metal, in diverse physiological processes, such as growth and development, maintenance and priming of the immune system, and tissue repair. This review will discuss aspects of Zn physiology and its possible beneficial role in the respiratory epithelium. Here we have detailed the mechanisms by which Zn diversely acts as: (i) an anti-oxidant; (ii) an organelle stabilizer; (iii) an anti-apopototic agent; (iv) an important cofactor for DNA synthesis; (v) a vital component for wound healing; and (vi) an anti-inflammatory agent. This paper will also review studies from the authors' laboratory concerning the first attempts to map Zn in the respiratory epithelium and to elucidate its role in regulating caspase-3 activated apoptosis. We propose that Zn, being a major dietary anti-oxidant has a protective role for the airway epithelium against oxyradicals and other noxious agents. Zn may therefore have important implications for asthma and other inflammatory diseases where the physical barrier is vulnerable and compromised.     

Semi-Automated Detection of Cerebral Microbleeds on 3.0 T MR Images

Cerebral microbleeds are associated with vascular disease and dementia. They can be detected on MRI and receive increasing attention. Visual rating is the current standard for microbleed detection, but is rater dependent, has limited reproducibility, modest sensitivity, and can be time-consuming. The goal of the current study is to present a tool for semi-automated detection of microbleeds that can assist human raters in the rating procedure. The radial symmetry transform is originally a technique to highlight circular-shaped objects in two-dimensional images. In the current study, the three-dimensional radial symmetry transform was adapted to detect spherical microbleeds in a series of 72 patients from our hospital, for whom a ground truth visual rating was made by four raters. Potential microbleeds were automatically identified on T2*-weighted 3.0 T MRI scans and the results were visually checked to identify microbleeds. Final ratings of the radial symmetry transform were compared to human ratings. After implementing and optimizing the radial symmetry transform, the method achieved a high sensitivity, while maintaining a modest number of false positives. Depending on the settings, sensitivities ranged from 65%–84% compared to the ground truth rating. Rating of the processed images required 1–2 minutes per participant, in which 20–96 false positive locations per participant were censored. Sensitivities of individual raters ranged from 39%–86% compared to the ground truth and required 5–10 minutes per participant per rater. The sensitivities that were achieved by the radial symmetry transform are similar to those of individual experienced human raters, demonstrating its feasibility and usefulness for semi-automated microbleed detection.     

Practical Methodology of Cognitive Tasks Within a Navigational Assessment

This paper describes an approach for measuring navigation accuracy relative to cognitive skills. The methodology behind the assessment will thus be clearly outlined in a step-by-step manner. Navigational skills are important when trying to find symbols within a speech-generating device (SGD) that has a dynamic screen and taxonomical organization. The following skills have been found to impact children’s ability to find symbols when navigating within the levels of an SGD: sustained attention, categorization, cognitive flexibility, and fluid reasoning^1,2. According to past studies, working memory was not correlated with navigation^1,2.The materials needed for this method include a computerized tablet, an augmentative and alternative communication application, a booklet of symbols, and the Leiter International Performance Scale-Revised (Leiter-R)³. This method has been used in two previous studies. Robillard, Mayer-Crittenden, Roy-Charland, Minor-Corriveau and Bélanger¹ assessed typically developing children, while Rondeau, Robillard and Roy-Charland² assessed children and adolescents with a diagnosis of Autism Spectrum Disorder. The direct observation of this method will facilitate the replication of this study for researchers. It will also help clinicians that work with children who have complex communication needs to determine the children’s ability to navigate an SGD with taxonomical categorization.     

Therapeutic Hypothermia Modifies Perinatal Asphyxia-Induced Changes of the Corpus Callosum and Outcome in Neonates

What Is Known about this Subject?

Diffusion-weighted MRI has demonstrated changes in the corpus callosum of term neonates with perinatal asphyxia. The severity of cerebral changes demonstrated using diffusion-weighted MRI is difficult to assess without measuring values of the Apparent Diffusion Coefficient (ADC).

What Is New?

ADC values of the anterior part of the corpus callosum are slightly higher than of the posterior part in full term infants with perinatal asphyxia. Low ADC values of the corpus callosum were associated with an adverse outcome in infants with perinatal asphyxia. In infants treated with hypothermia lower ADC values than with normothermia were associated with a poor outcome, supporting neuroprotective effects of hypothermia

Background

Using MRI, changes can be detected in the corpus callosum (CC) following perinatal asphyxia which are associated with later neurodevelopmental outcome.

Aim

To study the association between the apparent diffusion coefficient of water (ADC) in the CC on MRI in neonates with perinatal asphyxia and neurodevelopmental outcome at 18 months of age.

Subjects, Methods

Of 121 infants 32 (26%) died and 13 (11%) survived with an adverse neurological outcome. Sixty-five (54%) received therapeutic hypothermia. MRI was performed within 7 days after birth using a 1.5 T or 3.0 T system, and ADC values were measured in the anterior and posterior CC. The association between ADC and composite outcome (death or abnormal neurodevelopment) was analyzed for both normothermia and hypothermia cases using receiver operating characteristics.

Results

ADC values of the posterior CC were lower than of the anterior part (mean difference 0.050 x 10^-3 mm²/s, p<0.001). Field strength did not affect ADC values. ADC values of the posterior part of the CC were significantly lower in infants with basal ganglia/thalamus or near total brain injury (p<0.001). Lower ADC values were associated with an adverse outcome, but cut-off levels were lower after hypothermia (1.024 x 10^-3 mm²/s vs 0.969 x 10^-3 mm²/s)

Conclusion

Low ADC values of the posterior part of the corpus callosum are associated with an adverse outcome in term or near term neonates with perinatal asphyxia. Therapeutic hypothermia slightly modifies this association, showing that lower values were needed for an adverse outcome.     

Chimpanzee population structure in Cameroon and Nigeria is associated with habitat variation that may be lost under climate change

Background

The Nigeria-Cameroon chimpanzee (Pan troglodytes ellioti) is found in the Gulf of Guinea biodiversity hotspot located in western equatorial Africa. This subspecies is threatened by habitat fragmentation due to logging and agricultural development, hunting for the bushmeat trade, and possibly climate change. Although P. t. ellioti appears to be geographically separated from the neighboring central chimpanzee (P. t. troglodytes) by the Sanaga River, recent population genetics studies of chimpanzees from across this region suggest that additional factors may also be important in their separation. The main aims of this study were: 1) to model the distribution of suitable habitat for P. t. ellioti across Cameroon and Nigeria, and P. t. troglodytes in southern Cameroon, 2) to determine which environmental factors best predict their optimal habitats, and 3) to compare modeled niches and test for their levels of divergence from one another. A final aim of this study was to examine the ways that climate change might impact suitable chimpanzee habitat across the region under various scenarios.

Results

Ecological niche models (ENMs) were created using the software package Maxent for the three populations of chimpanzees that have been inferred to exist in Cameroon and eastern Nigeria: (i) P. t. troglodytes in southern Cameroon, (ii) P. t. ellioti in northwestern Cameroon, and (iii) P. t. ellioti in central Cameroon. ENMs for each population were compared using the niche comparison test in ENMtools, which revealed complete niche divergence with very little geographic overlap of suitable habitat between populations.

Conclusions

These findings suggest that a positive relationship may exist between environmental variation and the partitioning of genetic variation found in chimpanzees across this region. ENMs for each population were also projected under three different climate change scenarios for years 2020, 2050, and 2080. Suitable habitat of P. t. ellioti in northwest Cameroon / eastern Nigeria is expected to remain largely unchanged through 2080 in all considered scenarios. In contrast, P. t. ellioti in central Cameroon, which represents half of the population of this subspecies, is expected to experience drastic reductions in its ecotone habitat over the coming century.

Electronic supplementary material

The online version of this article (doi:10.1186/s12862-014-0275-z) contains supplementary material, which is available to authorized users.     

Alkaliphilus serpentinus sp. nov. and Alkaliphilus pronyensis sp. nov., two novel anaerobic alkaliphilic species isolated from the serpentinite-hosted Prony Bay Hydrothermal Field (New Caledonia)

Two novel anaerobic alkaliphilic strains, designated as LacT^T and LacV^T, were isolated from the Prony Bay Hydrothermal Field (PBHF, New Caledonia). Cells were motile, Gram-positive, terminal endospore-forming rods, displaying a straight to curved morphology during the exponential phase. Strains LacT^T and LacV^T were mesophilic (optimum 30 °C), moderately alkaliphilic (optimum pH 8.2 and 8.7, respectively) and halotolerant (optimum 2% and 2.5% NaCl, respectively). Both strains were able to ferment yeast extract, peptone and casamino acids, but only strain LacT^T could use sugars (glucose, maltose and sucrose). Both strains disproportionated crotonate into acetate and butyrate. Phylogenetic analysis revealed that strains LacT^T and LacV^T shared 96.4% 16S rRNA gene sequence identity and were most closely related to A. peptidifermentans Z-7036, A. namsaraevii X-07-2 and A. hydrothermalis FatMR1 (95.7%–96.3%). Their genome size was of 3.29 Mb for strain LacT^T and 3.06 Mb for strain LacV^T with a G + C content of 36.0 and 33.9 mol%, respectively. The ANI value between both strains was 73.2 %. Finally, strains LacT^T (=DSM 100337 = JCM 30643) and LacV^T (=DSM 100017 = JCM 30644) are proposed as two novel species of the genus Alkaliphilus, order Clostridiales, phylum Firmicutes, Alkaliphilus serpentinus sp. nov. and Alkaliphilus pronyensis sp. nov., respectively. The genomes of the three Alkaliphilus species isolated from PBHF were consistently detected in the PBHF chimney metagenomes, although at very low abundance, but not significantly in the metagenomes of other serpentinizing systems (marine or terrestrial) worldwide, suggesting they represent indigenous members of the PBHF microbial ecosystem.     

Arctic parasitology: why should we care?

The significant impact on human and animal health from parasitic infections in tropical regions is well known, but parasites of medical and veterinary importance are also found in the Arctic. Subsistence hunting and inadequate food inspection can expose people of the Arctic to foodborne parasites. Parasitic infections can influence the health of wildlife populations and thereby food security. The low ecological diversity that characterizes the Arctic imparts vulnerability. In addition, parasitic invasions and altered transmission of endemic parasites are evident and anticipated to continue under current climate changes, manifesting as pathogen range expansion, host switching, and/or disease emergence or reduction. However, Arctic ecosystems can provide useful models for understanding climate-induced shifts in host-parasite ecology in other regions.     

Wnt signaling regulates atrioventricular canal formation upstream of BMP and Tbx2

In the developing heart, the atrioventricular canal (AVC) is essential for separation and alignment of the cardiac chambers, for valve formation, and serves to delay the electrical impulse from the atria to the ventricles. Defects in various aspects of its formation are the most common form of congenital heart defects. Using mutant and transgenic approaches in zebrafish, this study demonstrates that Wnt/β-catenin signaling is both sufficient and required for the induction of BMP4 and Tbx2b expression in the AVC and consequently the proper patterning of the myocardium. Furthermore, genetic analysis shows that Wnt/β-catenin signaling is upstream and in a linear pathway with BMP and Tbx2 during AVC specification.