Weak association of anti-sperm antibodies and strong association of familial cryptorchidism/infertility with HLA-DRB1polymorphisms in prepubertal Ukrainian boys

<p>Abstract</p> <p>Background</p> <p>Cryptorchidism is a frequent syndrome occurring in 1-2% of males within the first year of age. Autoimmune reactions, particularly directed to testicular elements and/or spermatozoa have been found to be often associated with cryptorchidism. Therefore we investigated in this study the frequency of HLA class II alleles in order to recognize possible genetic predisposition for antisperm antibodies development in prepubertal boys with diagnosed cryptorchidism in Caucasoid population.</p> <p>Methods</p> <p>Sixty prepubertal boys with cryptorchidism and sixty healthy boys were examined for anti-sperm antibodies by indirect immunobead test as well as for their <it>HLA-DRB1 </it>and -<it>DQB1 </it>alleles using DNA obtained from peripheral blood leukocytes. The typing of <it>HLA-DRB1 </it>and -<it>DQB1 </it>was performed by using PCR-SSP low resolution method.</p> <p>Results</p> <p>Allele frequencies of <it>HLA-DRB1 </it>and <it>HLA-DQB1 </it>did not differ between boys with cryptorchidism and control boys. However, weakly significant differences in <it>DRB1*04 </it>(<it>p corrected </it>= 0.0475) and <it>DQB1*06 </it>(<it>p corrected </it>= 0.0385) were seen between cryptorchid patients with and without AsA, but none of these two patient groups differed significantly in <it>HLA </it>class II frequencies from controls except for AsA-negatives and <it>HLA-DQB1*06 </it>(<it>p corrected </it>= 0.0247). On the other hand, comparison of cryptorchid boys with familial cryptorchidism and/or infertility to control boys revealed highly significant (<it>p corrected </it>= 0.0006) difference in <it>HLA-DRB*11 </it>frequency, whereas boys with sporadic cryptorchidism did not differ from control. A much weaker, but still significant difference in <it>DRB*11 </it>frequency was also observed between boys with bilateral cryptorchidism and controls (<it>p corrected </it>= 0.037), whereas patients with unilateral cryptorchidism were not different from control in frequency of any <it>HLA-DRB1 </it>or -<it>DQB1 </it>allele tested.</p> <p>Conclusions</p> <p>Predisposition to produce anti-sperm antibodies seems to be only weakly associated with <it>HLA </it>class II genes, although this question requires further study on much larger population sample. It is plausible that familial and sporadic cryptorchidism may present distinct genetic background. The same may, to lower extent, apply to bilateral and unilateral cryptorchidism.</p

Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice

Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe−/−Neil3−/− mice on high-fat diet showed accelerated plaque formation as compared to Apoe−/− mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe−/−Neil3−/− mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage

Molecular Signatures in Arabidopsis thaliana in Response to Insect Attack and Bacterial Infection

Background Under the threat of global climatic change and food shortages, it is essential to take the initiative to obtain a comprehensive understanding of common and specific defence mechanisms existing in plant systems for protection against different types of biotic invaders. We have implemented an integrated approach to analyse the overall transcriptomic reprogramming and systems-level defence responses in the model plant species Arabidopsis thaliana (A. thaliana henceforth) during insect Brevicoryne brassicae (B. brassicae henceforth) and bacterial Pseudomonas syringae pv. tomato strain DC3000 (P. syringae henceforth) attacks. The main aim of this study was to identify the attacker-specific and general defence response signatures in A. thaliana when attacked by phloem-feeding aphids or pathogenic bacteria. Results The obtained annotated networks of differentially expressed transcripts indicated that members of transcription factor families, such as WRKY, MYB, ERF, BHLH and bZIP, could be crucial for stress-specific defence regulation in Arabidopsis during aphid and P. syringae attack. The defence response pathways, signalling pathways and metabolic processes associated with aphid attack and P. syringae infection partially overlapped. Components of several important biosynthesis and signalling pathways, such as salicylic acid (SA), jasmonic acid (JA), ethylene (ET) and glucosinolates, were differentially affected during the two the treatments. Several stress-regulated transcription factors were known to be associated with stress-inducible microRNAs. The differentially regulated gene sets included many signature transcription factors, and our co-expression analysis showed that they were also strongly co-expressed during 69 other biotic stress experiments. Conclusions Defence responses and functional networks that were unique and specific to aphid or P. syringae stresses were identified. Furthermore, our analysis revealed a probable link between biotic stress and microRNAs in Arabidopsis and, thus gives indicates a new direction for conducting large-scale targeted experiments to explore the detailed regulatory links between them. The presented results provide a comparative understanding of Arabidopsis – B. brassicae and Arabidopsis – P. syringae interactions at the transcriptomic level

Molecular Signatures in <i>Arabidopsis thaliana</i> in Response to Insect Attack and Bacterial Infection

<div><p>Background</p><p>Under the threat of global climatic change and food shortages, it is essential to take the initiative to obtain a comprehensive understanding of common and specific defence mechanisms existing in plant systems for protection against different types of biotic invaders. We have implemented an integrated approach to analyse the overall transcriptomic reprogramming and systems-level defence responses in the model plant species <i>Arabidopsis thaliana</i> (<i>A. thaliana</i> henceforth) during insect <i>Brevicoryne brassicae</i> (<i>B. brassicae</i> henceforth) and bacterial <i>Pseudomonas syringae pv. tomato strain DC3000</i> (<i>P. syringae</i> henceforth) attacks. The main aim of this study was to identify the attacker-specific and general defence response signatures in <i>A. thaliana</i> when attacked by phloem-feeding aphids or pathogenic bacteria.</p><p>Results</p><p>The obtained annotated networks of differentially expressed transcripts indicated that members of transcription factor families, such as <i>WRKY, MYB, ERF, BHLH and bZIP,</i> could be crucial for stress-specific defence regulation in <i>Arabidopsis</i> during aphid and <i>P. syringae</i> attack. The defence response pathways, signalling pathways and metabolic processes associated with aphid attack and <i>P. syringae</i> infection partially overlapped. Components of several important biosynthesis and signalling pathways, such as salicylic acid (SA), jasmonic acid (JA), ethylene (ET) and glucosinolates, were differentially affected during the two the treatments. Several stress-regulated transcription factors were known to be associated with stress-inducible microRNAs. The differentially regulated gene sets included many signature transcription factors, and our co-expression analysis showed that they were also strongly co-expressed during 69 other biotic stress experiments.</p><p>Conclusions</p><p>Defence responses and functional networks that were unique and specific to aphid or <i>P. syringae</i> stresses were identified. Furthermore, our analysis revealed a probable link between biotic stress and microRNAs in <i>Arabidopsis</i> and, thus gives indicates a new direction for conducting large-scale targeted experiments to explore the detailed regulatory links between them. The presented results provide a comparative understanding of <i>Arabidopsis</i> – <i>B. brassicae</i> and <i>Arabidopsis</i> – <i>P. syringae</i> interactions at the transcriptomic level.</p></div

Overall summary of the differentially regulated genes in <i>A. thaliana</i> during <i>Brevicoryne brassicae</i> (aphid) attack or <i>P. syringae</i> (bacteria) infection.

<p>Overall summary of the differentially regulated genes in <i>A. thaliana</i> during <i>Brevicoryne brassicae</i> (aphid) attack or <i>P. syringae</i> (bacteria) infection.</p

Regulatory overview map.

<p>MapMan regulatory overview map showing differences in transcript levels between aphid-specific and <i>P. syringae</i>-specific genes. Aphid-specific and <i>P. syringae</i>-specific bins are marked as ‘A’, and <i>P. syringae</i>-specific bins are marked as ‘P’. In the colour scale, blue represents higher gene expression, and red represents lower gene expression. IAA, Indole-3-acetic acid; ABA, abscisic acid; BA, brassinosteroid; SA, salicylic acid; MAP, mitogen-activated protein.</p

Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism

Cytosine methylation in CpG dinucleotides is an epigenetic DNA modification dynamically established and maintained by DNA methyltransferases and demethylases. Molecular mechanisms of active DNA demethylation began to surface only recently with the discovery of the 5-methylcytosine (5mC)-directed hydroxylase and base excision activities of ten–eleven translocation (TET) proteins and thymine DNA glycosylase (TDG). This implicated a pathway operating through oxidation of 5mC by TET proteins, which generates substrates for TDG-dependent base excision repair (BER) that then replaces 5mC with C. Yet, direct evidence for a productive coupling of TET with BER has never been presented. Here we show that TET1 and TDG physically interact to oxidize and excise 5mC, and proof by biochemical reconstitution that the TET–TDG–BER system is capable of productive DNA demethylation. We show that the mechanism assures a sequential demethylation of symmetrically methylated CpGs, thereby avoiding DNA double-strand break formation but contributing to the mutability of methylated CpGs

The 21 genes in the aphid-specific gene set known to be regulated by biotic stresses and their association with stress-inducible microRNAs.

<p>The 21 genes in the aphid-specific gene set known to be regulated by biotic stresses and their association with stress-inducible microRNAs.</p

Genes involved in glucosinolate metabolism affected by aphid infestation.

<p>Genes involved in glucosinolate metabolism affected by aphid infestation.</p

Functional targets of the microRNA families in the common set of genes (retrieved from literature searches).

<p>Functional targets of the microRNA families in the common set of genes (retrieved from literature searches).</p