Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes—the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes—we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10^-7) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.     

Differential effects of glucose deprivation on the cellular sensitivity towards photodynamic treatment-based production of reactive oxygen species and apoptosis-induction

Photodynamic treatment (PDT) employs a photosensitizer and the light-induced formation of reactive oxygen species--antagonized by cellular antioxidant systems--for the removal of harmful cells. This study addresses the effect of altered carbohydrate metabolism on the cellular antioxidant glutathione system, and the subsequent responses to PDT. It is shown that glucose-deprivation of 18 h prior to PDT causes a reduced level of intracellular glutathione and an increased cytotoxicity of PDT. These effects can be mimicked by inhibitors of glutathione synthesis (buthionine-sulfoximine) or its regeneration (1,3-bis-(2-chlorethyl)-1-nitrosourea). Inhibited glutathione metabolism shifts the apoptotic window to lower fluences, while glucose deprivation abolishes apoptosis as a result of ATP deficiency. Our results prove evidence for manipulation of the outcome of PDT through internal metabolic pathways.     

SEEDLING ESTABLISHMENT IN FORESTS AFFECTED BY TEPHRA FROM MOUNT ST. HELENS

Seedling density on permanent plots at five sites was monitored for the first four summers following the deposition of 4.5 to 15 cm of tephra from the 1980 eruption of Mount St. Helens. Because the old-growth forests at the sites were not destroyed by the volcanic eruption, the plots were under a normal tree canopy. Almost no seedlings established in 1980. By 1983 tree seedling density exceeded 35 m^−-2 at all sites. Tsuga heterophylla seedlings were most common, with Abies amabilis seedlings next in abundance. A dense layer of small trees may develop on the tephra and long-term forest dynamics could be affected. There was no successful invasion by species not already present in the stands. Seedlings of some forest herbs, especially Tiarella trifoliata, were common, but many other common forest species produced none. It is still problematical if or when these species will return to areas of the forest from which they were extirpated.     

Effects of landscape structure and land-use intensity on similarity of plant and animal communities

Aim Species richness in itself is not always sufficient to evaluate land management strategies for nature conservation. The exchange of species between local communities may be affected by landscape structure and land‐use intensity. Thus, species turnover, and its inverse, community similarity, may be useful measures of landscape integrity from a diversity perspective. Location A European transect from France to Estonia. Methods We measured the similarity of plant, bird, wild bee, true bug, carabid beetle, hoverfly and spider communities sampled along gradients in landscape composition (e.g. total availability of semi‐natural habitat), landscape configuration (e.g. fragmentation) and land‐use intensity (e.g. pesticide loads). Results Total availability of semi‐natural habitats had little effect on community similarity, except for bird communities, which were more homogeneous in more natural landscapes. Bee communities, in contrast, were less similar in landscapes with higher percentages of semi‐natural habitats. Increased landscape fragmentation decreased similarity of true bug communities, while plant communities showed a nonlinear, U‐shaped response. More intense land use, specifically increased pesticide burden, led to a homogenization of bee, bug and spider communities within sites. In these cases, habitat fragmentation interacted with pesticide load. Hoverfly and carabid beetle community similarity was differentially affected by higher pesticide levels: for carabid beetles similarity decreased, while for hoverflies we observed a U‐shaped relationship. Main conclusions Our study demonstrates the effects of landscape composition, configuration and land‐use intensity on the similarity of communities. It indicates reduced exchange of species between communities in landscapes dominated by agricultural activities. Taxonomic groups differed in their responses to environmental drivers and using but one group as an indicator for ‘biodiversity’ as such would thus not be advisable.     

Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens

Background

Noninvasive prenatal screening (NIPS) of common aneuploidies using cell-free DNA from maternal plasma is part of routine prenatal care and is widely used in both high-risk and low-risk patient populations. High specificity is needed for clinically acceptable positive predictive values. Maternal copy-number variants (mCNVs) have been reported as a source of false-positive aneuploidy results that compromises specificity.

Methods

We surveyed the mCNV landscape in 87,255 patients undergoing NIPS. We evaluated both previously reported and novel algorithmic strategies for mitigating the effects of mCNVs on the screen’s specificity. Further, we analyzed the frequency, length, and positional distribution of CNVs in our large dataset to investigate the curation of novel fetal microdeletions, which can be identified by NIPS but are challenging to interpret clinically.

Results

mCNVs are common, with 65% of expecting mothers harboring an autosomal CNV spanning more than 200 kb, underscoring the need for robust NIPS analysis strategies. By analyzing empirical and simulated data, we found that general, outlier-robust strategies reduce the rate of mCNV-caused false positives but not as appreciably as algorithms specifically designed to account for mCNVs. We demonstrate that large-scale tabulation of CNVs identified via routine NIPS could be clinically useful: together with the gene density of a putative microdeletion region, we show that the region’s relative tolerance to duplications versus deletions may aid the interpretation of microdeletion pathogenicity.

Conclusions

Our study thoroughly investigates a common source of NIPS false positives and demonstrates how to bypass its corrupting effects. Our findings offer insight into the interpretation of NIPS results and inform the design of NIPS algorithms suitable for use in screening in the general obstetric population.

     

Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inflammatory Signaling

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Cell type‐specific regulation of ciliary transition zone assembly in vertebrates

Ciliopathies are life‐threatening human diseases caused by defective cilia. They can often be traced back to mutations of genes encoding transition zone (TZ) proteins demonstrating that the understanding of TZ organisation is of paramount importance. The TZ consists of multimeric protein modules that are subject to a stringent assembly hierarchy. Previous reports place Rpgrip1l at the top of the TZ assembly hierarchy in Caenorhabditis elegans. By performing quantitative immunofluorescence studies in RPGRIP1L^?/? mouse embryos and human embryonic cells, we recognise a different situation in vertebrates in which Rpgrip1l deficiency affects TZ assembly in a cell type‐specific manner. In cell types in which the loss of Rpgrip1l alone does not affect all modules, additional truncation or removal of vertebrate‐specific Rpgrip1 results in an impairment of all modules. Consequently, Rpgrip1l and Rpgrip1 synergistically ensure the TZ composition in several vertebrate cell types, revealing a higher complexity of TZ assembly in vertebrates than in invertebrates.     

High climate velocity and population fragmentation may constrain climate‐driven range shift of the key habitat former Fucus vesiculosus

Aim

The Baltic Sea forms a unique regional sea with its salinity gradient ranging from marine to nearly freshwater conditions. It is one of the most environmentally impacted brackish seas worldwide, and the low biodiversity makes it particularly sensitive to anthropogenic pressures including climate change. We applied a novel combination of models to predict the fate of one of the dominant foundation species in the Baltic Sea, the bladder wrack Fucus vesiculosus.

Location

The Baltic Sea.

Methods

We used a species distribution model to predict climate change‐induced displacement of F. vesiculosus and combined these projections with a biophysical model of dispersal and connectivity to explore whether the dispersal rate of locally adapted genotypes may match estimated climate velocities to recolonize the receding salinity gradient. In addition, we used a population dynamic model to assess possible effects of habitat fragmentation.

Results

The species distribution model showed that the habitat of F. vesiculosus is expected to dramatically shrink, mainly caused by the predicted reduction of salinity. In addition, the dispersal rate of locally adapted genotypes may not keep pace with estimated climate velocities rendering the recolonization of the receding salinity gradient more difficult. A simplistic model of population dynamics also indicated that the risk of local extinction may increase due to future habitat fragmentation.

Main conclusions

Results point to a significant risk of locally adapted genotypes being unable to shift their ranges sufficiently fast considering the restricted dispersal and long generation time. The worst scenario is that F. vesiculosus may disappear from large parts of the Baltic Sea before the end of this century with large effects on the biodiversity and ecosystem functioning. We finally discuss how to reduce this risk through conservation actions, including assisted colonization and assisted evolution.     

Lolium perenne L. root systems are a collection of Gaussian curve shaped meso diameter class length distributions

Aims

Determine if the root system of Lolium perenne L. (L perenne) is a continuous distribution of diameters, or a collection of discrete diameters classes.

Methods

Plants from tillers of five clones were grown in a local soil amended with lime. Roots were excavated after they were grown in soil for 54 days, washed and imaged with both a commercial scanner (94 px mm^?1) and a high resolution, locally built, imager (204 px mm^?1). Images were converted to diameter class length data with WinRhizo.

Results

Scanned images did not have enough resolution to accurately measure fine roots diameters (<0.09 mm diam.). Therefore the high resolution images were used. The diameter class length distributions (DCLD) of these images demonstrated diameter class clusters (meso diameter classes) which could be modeled with a non-linear Gaussian (normal) curve model. Recreating the whole root system from a compilation of the DCLD, regenerated from the three parameters of each of the Gaussian curves for the root system, produced a distribution visually identical to the original whole root system curve.

Conclusions

L perenne root systems are a collection of meso diameter classes easily described by non-linear Gaussian models. The data set of the parameters from these models is much smaller than a WinRhizo data set, and can reconstruct the original whole system DCLD.     

Inhaled corticosteroid use is associated with increased circulating T regulatory cells in children with asthma

Background

T regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use.

Methods

Peripheral blood mononuclear cells from healthy control subjects (N?=?93) and asthmatic children of varying disease severity (N?=?66) were characterized by multi-parameter flow cytometry.

Results

Our findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma.

Conclusion

We conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency.