Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data

Contains fulltext : 89126.pdf (publisher's version ) (Open Access)BACKGROUND: Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. RESULTS: The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the Fc gamma RIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. CONCLUSIONS: Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. Availability: http://sourceforge.net/projects/sdrproject/

Acinetobacter baumannii Secretes Cytotoxic Outer Membrane Protein A via Outer Membrane Vesicles

Acinetobacter baumannii is an important nosocomial pathogen that causes a high morbidity and mortality rate in infected patients, but pathogenic mechanisms of this microorganism regarding the secretion and delivery of virulence factors to host cells have not been characterized. Gram-negative bacteria naturally secrete outer membrane vesicles (OMVs) that play a role in the delivery of virulence factors to host cells. A. baumannii has been shown to secrete OMVs when cultured in vitro, but the role of OMVs in A. baumannii pathogenesis is not well elucidated. In the present study, we evaluated the secretion and delivery of virulence factors of A. baumannii to host cells via the OMVs and assessed the cytotoxic activity of outer membrane protein A (AbOmpA) packaged in the OMVs. A. baumannii ATCC 19606T secreted OMVs during in vivo infection as well as in vitro cultures. Potential virulence factors, including AbOmpA and tissue-degrading enzymes, were associated with A. baumannii OMVs. A. baumannii OMVs interacted with lipid rafts in the plasma membranes and then delivered virulence factors to host cells. The OMVs from A. baumannii ATCC 19606T induced apoptosis of host cells, whereas this effect was not detected in the OMVs from the ΔompA mutant, thereby reflecting AbOmpA-dependent host cell death. The N-terminal region of AbOmpA22-170 was responsible for host cell death. In conclusion, the OMV-mediated delivery of virulence factors to host cells may well contribute to pathogenesis during A. baumannii infection

Between China and South Asia: A Middle Asian corridor of crop dispersal and agricultural innovation in the Bronze Age

© The Author(s) 2016. The period from the late third millennium BC to the start of the first millennium AD witnesses the first steps towards food globalization in which a significant number of important crops and animals, independently domesticated within China, India, Africa and West Asia, traversed Central Asia greatly increasing Eurasian agricultural diversity. This paper utilizes an archaeobotanical database (AsCAD), to explore evidence for these crop translocations along southern and northern routes of interaction between east and west. To begin, crop translocations from the Near East across India and Central Asia are examined for wheat (Triticum aestivum) and barley (Hordeum vulgare) from the eighth to the second millennia BC when they reach China. The case of pulses and flax (Linum usitatissimum) that only complete this journey in Han times (206 BC–AD 220), often never fully adopted, is also addressed. The discussion then turns to the Chinese millets, Panicum miliaceum and Setaria italica, peaches (Amygdalus persica) and apricots (Armeniaca vulgaris), tracing their movement from the fifth millennium to the second millennium BC when the Panicum miliaceum reaches Europe and Setaria italica Northern India, with peaches and apricots present in Kashmir and Swat. Finally, the translocation of japonica rice from China to India that gave rise to indica rice is considered, possibly dating to the second millennium BC. The routes these crops travelled include those to the north via the Inner Asia Mountain Corridor, across Middle Asia, where there is good evidence for wheat, barley and the Chinese millets. The case for japonica rice, apricots and peaches is less clear, and the northern route is contrasted with that through northeast India, Tibet and west China. Not all these journeys were synchronous, and this paper highlights the selective long-distance transport of crops as an alternative to demic-diffusion of farmers with a defined crop package

Pre-symptomatic transcriptome changes during cold storage of chilling sensitive and resistant peach cultivars to elucidate chilling injury mechanisms

Background: Cold storage induces chilling injury (CI) disorders in peach fruit (woolliness/mealiness, flesh browning and reddening/bleeding) manifested when ripened at shelf life. To gain insight into the mechanisms underlying CI, we analyzed the transcriptome of 'Oded' (high tolerant) and 'Hermoza' (relatively tolerant to woolliness, but sensitive to browning and bleeding) peach cultivars at pre-symptomatic stages. The expression profiles were compared and validated with two previously analyzed pools (high and low sensitive to woolliness) from the Pop-DG population. The four fruit types cover a wide range of sensitivity to CI. The four fruit types were also investigated with the ROSMETER that provides information on the specificity of the transcriptomic response to oxidative stress. Results: We identified quantitative differences in a subset of core cold responsive genes that correlated with sensitivity or tolerance to CI at harvest and during cold storage, and also subsets of genes correlating specifically with high sensitivity to woolliness and browning. Functional analysis indicated that elevated levels, at harvest and during cold storage, of genes related to antioxidant systems and the biosynthesis of metabolites with antioxidant activity correlates with tolerance. Consistent with these results, ROSMETER analysis revealed oxidative stress in 'Hermoza' and the progeny pools, but not in the cold resistant 'Oded'. By contrast, cold storage induced, in sensitivity to woolliness dependant manner, a gene expression program involving the biosynthesis of secondary cell wall and pectins. Furthermore, our results indicated that while ethylene is related to CI tolerance, differential auxin subcellular accumulation and signaling may play a role in determining chilling sensitivity/tolerance. In addition, sugar partitioning and demand during cold storage may also play a role in the tolerance/sensitive mechanism. The analysis also indicates that vesicle trafficking, membrane dynamics and cytoskeleton organization could have a role in the tolerance/sensitive mechanism. In the case of browning, our results suggest that elevated acetaldehyde related genes together with the core cold responses may increase sensitivity to browning in shelf life. Conclusions: Our data suggest that in sensitive fruit a cold response program is activated and regulated by auxin distribution and ethylene and these hormones have a role in sensitivity to CI even before fruit are cold stored.This research was funded by US-Israel Binational Agriculture Research and Development Fund (BARD) Grant no. 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Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. METHODS: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. RESULTS: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. CONCLUSIONS: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs

Analysis of TIMP-1 gene polymorphisms in Italian sclerodermic patients.

Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and internal organs fibrosis due to an extracellular matrix (ECM) accumulation of type I collagen. The turnover of the ECM is dependent on the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). The disruption of this balance is involved in SSc because higher serum TIMP-1 levels have been demonstrated in SSc patients than in controls. On this basis, we analyzed three polymorphisms: -19A&rt;G, +261C&rt;T, and +372T&rt;C of the TIMP-1 gene in SSc patients (67 females, eight males) and controls (29 females, nine males). The C allele of the +372T&rt;C single nucleotide polymorphism (SNP) was observed at a higher frequency in male patients than in healthy individuals (P= 0,02), while no differences were observed in the female subjects. Our findings suggest that the +372T&rt;C polymorphism of the TIMP-1 gene is associated with SSc in male individuals. No association with the clinical characteristics of SSc Italian patients and TIMP-1 gene polymorphisms was observed. Thus, the role of TIMP-1 gene in predisposition to SSc remains controversial