NF-κB in the regulation of epithelial homeostasis and inflammation

The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.     

Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra

Background

Recent attention has focused on understanding the role of the brain-renin-angiotensin-system (RAS) in stroke and neurodegenerative diseases. Direct evidence of a role for the brain-RAS in Parkinson's disease (PD) comes from studies demonstrating the neuroprotective effect of RAS inhibitors in several neurotoxin based PD models. In this study, we show that an antagonist of the angiotensin II (Ang II) type 1 (AT₁) receptor, losartan, protects dopaminergic (DA) neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity both in primary ventral mesencephalic (VM) cultures as well as in the substantia nigra pars compacta (SNpc) of C57BL/6 mice (Fig. 1).

Results

In the presence of exogenous Ang II, losartan reduced MPP⁺ (5 μM) induced DA neuronal loss by 72% in vitro. Mice challenged with MPTP showed a 62% reduction in the number of DA neurons in the SNpc and a 71% decrease in tyrosine hydroxylase (TH) immunostaining of the striatum, whereas daily treatment with losartan lessened MPTP-induced loss of DA neurons to 25% and reduced the decrease in striatal TH⁺ immunostaining to 34% of control.

Conclusion

Our study demonstrates that the brain-RAS plays an important neuroprotective role in the MPTP model of PD and points to AT₁ receptor as a potential novel target for neuroprotection.     

Metabolomics standards initiative: ontology working group work in progress

In this article we present the activities of the Ontology Working Group (OWG) under the Metabolomics Standards Initiative (MSI) umbrella. Our endeavour aims to synergise the work of several communities, where independent activities are underway to develop terminologies and databases for metabolomics investigations. We have joined forces to rise to the challenges associated with interpreting and integrating experimental process and data across disparate sources (software and databases, private and public). Our focus is to support the activities of the other MSI working groups by developing a common semantic framework to enable metabolomics-user communities to consistently annotate the experimental process and to enable meaningful exchange of datasets. Our work is accessible via a public webpage and a draft ontology has been posted under the Open Biological Ontology umbrella. At the very outset, we have agreed to minimize duplications across omics domains through extensive liaisons with other communities under the OBO Foundry. This is work in progress and we welcome new participants willing to volunteer their time and expertise to this open effort. See the MSI Ontology Working Group website for a complete list of members and contributors. Web URL:     

A Simple Genetic Architecture Underlies Morphological Variation in Dogs

Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (≤3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.     

Fitness reduction and potential extinction of wild populations of Atlantic salmon, Salmo salar, as a result of interactions with escaped farm salmon

The high level of escapes from Atlantic salmon farms, up to two million fishes per year in the North Atlantic, has raised concern about the potential impact on wild populations. We report on a two-generation experiment examining the estimated lifetime successes, relative to wild natives, of farm, F(1) and F(2) hybrids and BC(1) backcrosses to wild and farm salmon. Offspring of farm and "hybrids" (i.e. all F(1), F(2) and BC(1) groups) showed reduced survival compared with wild salmon but grew faster as juveniles and displaced wild parr, which as a group were significantly smaller. Where suitable habitat for these emigrant parr is absent, this competition would result in reduced wild smolt production. In the experimental conditions, where emigrants survived downstream, the relative estimated lifetime success ranged from 2% (farm) to 89% (BC(1) wild) of that of wild salmon, indicating additive genetic variation for survival. Wild salmon primarily returned to fresh water after one sea winter (1SW) but farm and 'hybrids' produced proportionately more 2SW salmon. However, lower overall survival means that this would result in reduced recruitment despite increased 2SW fecundity. We thus demonstrate that interaction of farm with wild salmon results in lowered fitness, with repeated escapes causing cumulative fitness depression and potentially an extinction vortex in vulnerable populations.     

A carbohydrate-rich diet increases social immunity in ants

Increased potential for disease transmission among nest-mates means living in groups has inherent costs. This increased potential is predicted to select for disease resistance mechanisms that are enhanced by cooperative exchanges among group members, a phenomenon known as social immunity. One potential mediator of social immunity is diet nutritional balance because traits underlying immunity can require different nutritional mixtures. Here, we show how dietary protein–carbohydrate balance affects social immunity in ants. When challenged with a parasitic fungus Metarhizium anisopliae, workers reared on a high-carbohydrate diet survived approximately 2.8× longer in worker groups than in solitary conditions, whereas workers reared on an isocaloric, high-protein diet survived only approximately 1.3× longer in worker groups versus solitary conditions. Nutrition had little effect on social grooming, a potential mechanism for social immunity. However, experimentally blocking metapleural glands, which secrete antibiotics, completely eliminated effects of social grouping and nutrition on immunity, suggesting a causal role for secretion exchange. A carbohydrate-rich diet also reduced worker mortality rates when whole colonies were challenged with Metarhizium. These results provide a novel mechanism by which carbohydrate exploitation could contribute to the ecological dominance of ants and other social groups.     

A Simple Isothermal DNA Amplification Method to Screen Black Flies for Onchocerca volvulus Infection

Onchocerciasis is a debilitating neglected tropical disease caused by infection with the filarial parasite Onchocerca volvulus. Adult worms live in subcutaneous tissues and produce large numbers of microfilariae that migrate to the skin and eyes. The disease is spread by black flies of the genus Simulium following ingestion of microfilariae that develop into infective stage larvae in the insect. Currently, transmission is monitored by capture and dissection of black flies and microscopic examination of parasites, or using the polymerase chain reaction to determine the presence of parasite DNA in pools of black flies. In this study we identified a new DNA biomarker, encoding O. volvulus glutathione S-transferase 1a (OvGST1a), to detect O. volvulus infection in vector black flies. We developed an OvGST1a-based loop-mediated isothermal amplification (LAMP) assay where amplification of specific target DNA is detectable using turbidity or by a hydroxy naphthol blue color change. The results indicated that the assay is sensitive and rapid, capable of detecting DNA equivalent to less than one microfilaria within 60 minutes. The test is highly specific for the human parasite, as no cross-reaction was detected using DNA from the closely related and sympatric cattle parasite Onchocerca ochengi. The test has the potential to be developed further as a field tool for use in the surveillance of transmission before and after implementation of mass drug administration programs for onchocerciasis.     

Accelerating regrowth of temperate‐maritime forests due to environmental change

To understand how environmental changes have influenced forest productivity, stemwood biomass (B) dynamics were analyzed at 1267 permanent inventory plots, covering a combined 209 ha area of unmanaged temperate‐maritime forest in southwest British Columbia, Canada. Net stemwood production (ΔB) was derived from periodic remeasurements of B collected over a 40‐year measurement period (1959–1998) in stands ranging from 20 to 150 years old. Comparison between the integrated age response of net stemwood production, ΔB(A), and the age response of stemwood biomass, B(A), suggested a 58 ± 11% increase in ΔB between the first 40 years of the chronosequence period (1859–1898) and the measurement period. To estimate extrinsic forcing on ΔB, several different candidate models were developed to remove variation explained by intrinsic factors. All models exhibited temporal bias, with positive trends in (observed minus predicted) residual ΔB ranging between of 0.40 and 0.64% yr^?1. Applying the same methods to stemwood growth (G) indicated residual increases ranging from 0.43 and 0.67% yr^?1. Higher trend estimates corresponded with models that included site index (SI) as a predictor, which may reflect exaggeration of the age‐decline in SI tables. Choosing a model that excluded SI, suggested that ΔB increased by 0.40 ± 0.18% yr^?1, while G increased by 0.43 ± 0.12% yr^?1 over the measurement period. Residual G was significantly correlated with atmospheric carbon dioxide (CO₂), temperature (T), and climate moisture index (CMI). However, models driven with climate and CO₂, alone, could not simultaneously explain long‐term and measurement‐period trends without additional representation of indirect effects, perhaps reflecting compound interest on direct physiological responses to environmental change. Evidence of accelerating forest regrowth highlights the value of permanent inventories to detect and understand systematic changes in forest productivity caused by environmental change.