Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3

Background: We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data. Method and results: A panel of congenic sub-strains were generated containing Wistar-Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function. Conclusion: This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge

Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling

Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation

A Full Variational Calculation Based on a Tensor ProductDecomposition

A new direct full variational approach exploits a tensor (Kronecker) product decomposition of the Hamiltonian. Explicit assembly and storage of the Hamiltonian matrix is avoided by using the Kronecker product structure to form matrix-vector products directly from the molecular integrals. Computation-intensive integral transformations and formula tapes are unnecessary. The wavefunction is expanded in terms of spin-free primitive kets rather than Staler determinants of configuration state functions, and the expansion is equivalent to a full configuration interaction expansion. The approach suggests compact storage schemes and algorithms which are naturally suited to parallel and pipelined machines

Differential expression of microRNA-206 and its target genes in pre-eclampsia

Objectives: Pre-eclampsia is a multi-system disease that significantly contributes to maternal and fetal morbidity and mortality. In this study, we used a non-biased microarray approach to identify novel circulating miRNAs in maternal plasma that may be associated with pre-eclampsia. Methods: Plasma samples were obtained at 16 and 28 weeks of gestation from 18 women who later developed pre-eclampsia (cases) and 18 matched women with normotensive pregnancies (controls). We studied miRNA expression profiles in plasma and subsequently confirmed miRNA and target gene expression in placenta samples. Placental samples were obtained from an independent cohort of 19 women with pre-eclampsia matched with 19 women with normotensive pregnancies. Results: From the microarray, we identified 1 miRNA that was significantly differentially expressed between cases and controls at 16 weeks of gestation and 6 miRNAs that were significantly differentially expressed at 28 weeks. Following qPCR validation only one, miR-206, was found to be significantly increased in 28 week samples in women who later developed pre-eclampsia (1.4 fold change ± 0.2). The trend for increase in miR-206 expression was mirrored within placental tissue from women with pre-eclampsia. In parallel, IGF-1, a target gene of miR-206, was also found to be down-regulated (0.41 ± 0.04) in placental tissue from women with pre-eclampsia. miR-206 expression was also detectable in myometrium tissue and trophoblast cell lines. Conclusions: Our pilot study has identified miRNA-206 as a novel factor up-regulated in pre-eclampsia within the maternal circulation and in placental tissue

Exome analysis of patients with concurrent pediatric inflammatory bowel disease (PIBD) and autoimmune disease

BACKGROUND: Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients. METHODS: Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test. RESULTS: Forty-nine (28.3%) PIBD children (18.49% CD, 8.6% UC, and 21.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed 6 significant genes (P < 0.05) before Bonferroni adjustment. Three of these genes were previously implicated in both asthma and IBD (ZPBP2 IL1R1, and IL18R1) and 3 in asthma only (PYHIN1, IL2RB, and GSTP1). CONCLUSIONS: One-third of our cohort had a concurrent autoimmune condition. We observed higher incidence of asthma compared with the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests that a systemic immune dysregulation rather than organ-specific could underpin immune dysfunction for a subset of patients

How inert, perturbing, or interacting are cryogenic matrices? A combined spectroscopic (infrared, electronic, and x-ray absorption) and DFT investigation of matrix-isolated Iron, Cobalt, Nickel, and Zinc Dibromides

The interactions of FeBr2, CoBr2, NiBr2 and ZnBr2 with Ne, Ar, Kr, Xe, CH4 and N2 matrices have been investigated using IR, electronic absorption and X-ray absorption spectroscopies, as well as DFT calculations. ZnBr2 is linear in all the matrices. NiBr2 is linear in all but N2 matrices where it is severely bent. For FeBr2 and CoBr2 there is a more gradual change, with evidence of non-linearity in Xe and CH4 matrices as well as N2. In the N2 matrices the presence of νNN modes blue shifted from the “free” N2 values indicates the presence of physisorbed species, and the magnitude of the blue-shift correlates with the shift in the ν3 mode of the metal dibromide. In the case of NiCl2 and NiBr2 chemisorbed species are formed after photolysis, but only if deposition takes place below 10 K. There was no evidence for chemisorbed species for NiF2 and FeBr2 and in the case of CoBr2 the evidence was not strong

An Alternative to Full Configuration Interaction Based on a Tensor Product Decomposition

A new direct full variational approach exploits a tensor (Kronecker) product decompositions of the Hamiltonian. Explicit assembly and storage of the Hamiltonian matrix is avoided by using the Kronecker product structure to form matrix-vector products directly from the molecular integrals. Computation-intensive integral transformations and formula tapes are unnecessary. The wave function is expanded in terms of spin-free primitive sets rather than Slater determinants or configuration state functions and is equivalent to a full configuration interaction expansion. The approach suggests compact storage schemes and algorithms which are naturally suited to parallel and pipelined machines