Evidence for genetic association of TBX21 and IFNG with systemic lupus erythematosus in a Chinese Han population

TBX21 recode T-bet which is an important transcription factor that drives the Th1 immune response primarily by promoting expression of the interferon-gamma (IFNG) gene. Recent studies have shown that genetic variants in TBX21 and IFNG are connected with risk of systemic lupus erythematosus (SLE). The aim of the present study was to replicate these genetic associations with SLE in Anhui Chinese population. Genotyping of 3 variants (rs4794067 in TBX21, rs2069705 and rs2069718 in IFNG) was performed. A total of 3732 subjects were included in the final analysis. The study only identified the association of rs2069705 with SLE susceptibility (T vs. C: odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.00-1.26, P = 0.046). Combined analysis with Hong Kong GWAS showed that the OR for rs2069705 was 1.10 (95% CI: 1.01-1.21, P = 0.027). Further pooled analysis with Korean populations involving 10498 subjects showed a more significant association between rs2069705 and SLE (T vs. C: OR = 1.11, 95%CI = 1.04-1.19, P = 0.002; TT + TC vs. CC: OR = 1.11, 95%CI = 1.02-1.21, P = 0.012; TT vs. TC + CC: OR = 1.28, 95%CI = 1.07-1.54, P = 0.008; TT vs. CC: OR = 1.33, 95%CI = 1.10-1.60, P = 0.003). In addition, we also identified a significant genetic interaction between rs2069705 and rs4794067 in Anhui Chinese population. Our study suggests that IFNG and IFNG-TBX21 interaction are involved in SLE susceptibility.published_or_final_versio

Digit-only sauropod pes trackways from China - evidence of swimming or a preservational phenomenon?

For more than 70 years unusual sauropod trackways have played a pivotal role in debates about the swimming ability of sauropods. Most claims that sauropods could swim have been based on manus-only or manus-dominated trackways. However none of these incomplete trackways has been entirely convincing, and most have proved to be taphonomic artifacts, either undertracks or the result of differential depth of penetration of manus and pes tracks, but otherwise showed the typical pattern of normal walking trackways. Here we report an assemblage of unusual sauropod tracks from the Lower Cretaceous Hekou Group of Gansu Province, northern China, characterized by the preservation of only the pes claw traces, that we interpret as having been left by walking, not buoyant or swimming, individuals. They are interpreted as the result of animals moving on a soft mud-silt substrate, projecting their claws deeply to register their traces on an underlying sand layer where they gained more grip during progression. Other sauropod walking trackways on the same surface with both pes and manus traces preserved, were probably left earlier on relatively firm substrates that predated the deposition of soft mud and silt . Presently, there is no convincing evidence of swimming sauropods from their trackways, which is not to say that sauropods did not swim at all

New Mouse Lines for the Analysis of Neuronal Morphology Using CreER(T)/loxP-Directed Sparse Labeling

BACKGROUND: Pharmacologic control of Cre-mediated recombination using tamoxifen-dependent activation of a Cre-estrogen receptor ligand binding domain fusion protein [CreER(T)] is widely used to modify and/or visualize cells in the mouse. METHODS AND FINDINGS: We describe here two new mouse lines, constructed by gene targeting to the Rosa26 locus to facilitate Cre-mediated cell modification. These lines should prove particularly useful in the context of sparse labeling experiments. The R26rtTACreER line provides ubiquitous expression of CreER under transcriptional control by the tetracycline reverse transactivator (rtTA); dual control by doxycycline and tamoxifen provides an extended dynamic range of Cre-mediated recombination activity. The R26IAP line provides high efficiency Cre-mediated activation of human placental alkaline phosphatase (hPLAP), complementing the widely used, but low efficiency, Z/AP line. By crossing with mouse lines that direct cell-type specific CreER expression, the R26IAP line has been used to produce atlases of labeled cholinergic and catecholaminergic neurons in the mouse brain. The R26IAP line has also been used to visualize the full morphologies of retinal dopaminergic amacrine cells, among the largest neurons in the mammalian retina. CONCLUSIONS: The two new mouse lines described here expand the repertoire of genetically engineered mice available for controlled in vivo recombination and cell labeling using the Cre-lox system

Evolution of the TGF-β Signaling Pathway and Its Potential Role in the Ctenophore, Mnemiopsis leidyi

The TGF-β signaling pathway is a metazoan-specific intercellular signaling pathway known to be important in many developmental and cellular processes in a wide variety of animals. We investigated the complexity and possible functions of this pathway in a member of one of the earliest branching metazoan phyla, the ctenophore Mnemiopsis leidyi. A search of the recently sequenced Mnemiopsis genome revealed an inventory of genes encoding ligands and the rest of the components of the TGF-β superfamily signaling pathway. The Mnemiopsis genome contains nine TGF-β ligands, two TGF-β-like family members, two BMP-like family members, and five gene products that were unable to be classified with certainty. We also identified four TGF-β receptors: three Type I and a single Type II receptor. There are five genes encoding Smad proteins (Smad2, Smad4, Smad6, and two Smad1s). While we have identified many of the other components of this pathway, including Tolloid, SMURF, and Nomo, notably absent are SARA and all of the known antagonists belonging to the Chordin, Follistatin, Noggin, and CAN families. This pathway likely evolved early in metazoan evolution as nearly all components of this pathway have yet to be identified in any non-metazoan. The complement of TGF-β signaling pathway components of ctenophores is more similar to that of the sponge, Amphimedon, than to cnidarians, Trichoplax, or bilaterians. The mRNA expression patterns of key genes revealed by in situ hybridization suggests that TGF-β signaling is not involved in ctenophore early axis specification. Four ligands are expressed during gastrulation in ectodermal micromeres along all three body axes, suggesting a role in transducing earlier maternal signals. Later expression patterns and experiments with the TGF-β inhibitor SB432542 suggest roles in pharyngeal morphogenesis and comb row organization

Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus

INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, the detailed information for SLE association and the underlying functional mechanism(s) are still lacking. METHODS: Through meta-analysis of two genome-wide association studies (GWAS) on Chinese Han populations with a total of 1659 cases and 3398 controls matched geographically, we closely examined this region, especially on the reported single nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant association SNP with SLE using 2612 cases and 2323 controls of Asian ancestry. RESULTS: All reported SNPs in this region with different autoimmune diseases were examined in the two GWAS data and meta- analysis result, and supportive evidence of association with SLE was found (meta-analysis P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta = 2.70E-09). It showed independent effect through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand with a total of 2612 cases and 2323 controls (joint analysis of GWAS and replication result P_all = 1.31E-11, OR = 1.23). SNP rs2298428 was shown to be an eQTL for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in SLE cases. CONCLUSIONS: Association to distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms by these diseases.published_or_final_versio

Gene-Based Meta-Analysis of Genome-Wide Association Study Data Identifies Independent Single-Nucleotide Polymorphisms in ANXA6 as Being Associated With Systemic Lupus Erythematosus in Asian Populations

Objective Previous genome-wide association studies (GWAS), which were mainly based on single-variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene-based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants. Methods Based on the results of a meta-analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in-depth gene-based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing. Results More than one-half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously. Conclusion Our study demonstrated the merit of using gene-based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes. © 2015, American College of Rheumatology.postprin

An outbreak of cardiovascular syndromes requiring urgent medical treatment and its association with environmental factors: an ecological study

<p>Abstract</p> <p>Background</p> <p>In April 2005, syndromic surveillance based on statistical control chart methods in Sydney, Australia, signalled increasing incidence of urgent emergency department visits for cardiovascular and chest pain syndromes compared to the preceding twelve months. This paper aimed to determine whether environmental factors could have been responsible for this 'outbreak'.</p> <p>Methods</p> <p>The outcome studied was daily counts of emergency department visits for cardiovascular or chest pain syndromes that were considered immediately or imminently life threatening on arrival at hospital. The outbreak had a mean daily count of 5.7 visits sustained for eight weeks, compared with 4.0 in the same months in previous years. Poisson regression was used to systematically assess the emergency department visits in relation to available daily weather and pollution variables by first finding the best model that explained short-term variation in the outcome over the period 25 January 2002 to 31 May 2005, and then assessing interactions of all available variables with the 'outbreak' period, April-May 2005. Rate ratios were estimated for an interquartile increase in each variable meaning that the ratio measures the relative increase (or decrease) in the emergency department visits for an interquartile increase in the weather or pollution variable. The rate ratios for the outbreak period measure the relative increase (or decrease) in the emergency department visits for an interquartile increase in the weather or pollution variable during the outbreak period only.</p> <p>Results</p> <p>The best fitting model over the whole study period included minimum temperature with a rate ratio (RR) of 0.86 (95% confidence interval (CI), 0.77–0.96), maximum relative humidity of 1.09 (95% CI 1.05–1.14) and minimum daily particulate matter less than 10 microns (PM₁₀) of 1.05 (95% CI, 1.01–1.09). During the outbreak period, maximum temperature (RR 1.27, 95% CI 1.03–1.57), solar radiation (RR 1.44, 95% CI, 1.00–2.07) and ozone (RR 1.13, 95% CI 1.01–1.26) were associated with the outcome.</p> <p>Conclusion</p> <p>The increase may have been associated with photochemical pollution. Syndromic surveillance can identify outbreaks of non-communicable diseases associated with environmental factors.</p

Association study of genetic variants of pro-inflammatory chemokine and cytokine genes in systemic lupus erythematosus

BACKGROUND: Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory development and progression of systemic lupus erythematosus. The aim of this study was to evaluate the relevance of functional genetic variations of RANTES, IL-8, IL-1α, and MCP-1 for systemic lupus erythematosus. METHODS: The study was conducted on 500 SLE patients and 481 ethnically matched healthy controls. Genotyping of polymorphisms in the RANTES, IL-8, IL-1α, and MCP-1 genes were performed using a real-time polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. RESULTS: No significant differences between SLE patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the RANTES, IL-8, IL-1α, and MCP-1 polymorphisms. In addition, no evidence for association with clinical sub-features of SLE was found. CONCLUSION: These results suggest that the tested functional variation of RANTES, IL-8, IL-1α, and MCP-1 genes do not confer a relevant role in the susceptibility or severity of SLE in the Spanish population

Virus-Induced Gene Silencing as a Tool for Comparative Functional Studies in Thalictrum

Perennial woodland herbs in the genus Thalictrum exhibit high diversity of floral morphology, including four breeding and two pollination systems. Their phylogenetic position, in the early-diverging eudicots, makes them especially suitable for exploring the evolution of floral traits and the fate of gene paralogs that may have shaped the radiation of the eudicots. A current limitation in evolution of plant development studies is the lack of genetic tools for conducting functional assays in key taxa spanning the angiosperm phylogeny. We first show that virus-induced gene silencing (VIGS) of a PHYTOENE DESATURASE ortholog (TdPDS) can be achieved in Thalictrum dioicum with an efficiency of 42% and a survival rate of 97%, using tobacco rattle virus (TRV) vectors. The photobleached leaf phenotype of silenced plants significantly correlates with the down-regulation of endogenous TdPDS (P<0.05), as compared to controls. Floral silencing of PDS was achieved in the faster flowering spring ephemeral T. thalictroides. In its close relative, T. clavatum, silencing of the floral MADS box gene AGAMOUS (AG) resulted in strong homeotic conversions of floral organs. In conclusion, we set forth our optimized protocol for VIGS by vacuum-infiltration of Thalictrum seedlings or dormant tubers as a reference for the research community. The three species reported here span the range of floral morphologies and pollination syndromes present in Thalictrum. The evidence presented on floral silencing of orthologs of the marker gene PDS and the floral homeotic gene AG will enable a comparative approach to the study of the evolution of flower development in this group