Novel long non-coding RNAs of relevance for ulcerative colitis pathogenesis

Background and aims: The study aimed to identify yet unknown and uncharacterized long non-coding RNAs (lncRNAs) in treatment-naïve ulcerative colitis (UC), and to define their possible roles in UC pathogenesis. For that purpose, accurate quantification methods for lncRNA transcript detection, multiple and “stringent” strategies were applied. New insights in the regulation of functional genes and pathways of relevance for UC through expression of lncRNAs are expected. Methods: The study was based on sequencing data derived from a data set consisting of treatment-naïve UC patients (n = 14) and control subjects (n = 16). Two complementary aligners were used to identify lncRNAs. Several different steps were used to validate differential expression including plotting the reads over the annotation for manual inspection. To help determine potential lncRNA involvement in biological processes, KEGG pathway enrichment was done on protein-coding genes which co-expressed with the lncRNAs. Results: A total of 99 lncRNAs were identified in UC. The lncRNAs which were not previously characterized (n = 15) in UC or other autoimmune diseases were selected for down-stream analysis. In total, 602 protein-coding genes correlated with the uncharacterized lncRNAs. KEGG pathway enrichment analysis revealed involvement of lncRNAs in two significantly enriched pathways, lipid and atherosclerosis, and T-cell receptor signaling. Conclusion: This study identified a set of 15 yet uncharacterized lncRNAs which may be of importance for UC pathogenesis. These lncRNAs may serve as potential diagnostic biomarkers and might be of use for the development of UC treatment strategies in the future

Novel long-coding RNAs of relevance for ulcerative colitis pathogenesis

Poster presented at the Norwegian Bioinformatics Days 2022, Sundvolden, 28-30 September 2022.Introduction - LncRNAs have become a growing field of research. They are involved in diverse biological processes including expression regulation, and chromatin modification. Many lncRNAs have been characterized as involved in the occurrence and development of various human diseases, including cancer. A growing body of evidence implies a role for lncRNAs in UC by modulating the intestinal barrier, regulating the expression of inflammatory cytokines, and polarization of macrophages. Problems - Accurate quantification of lncRNA transcripts is challenging due to the low expression of lncRNAs, and their exons overlap protein-coding exons on the same strand. Aims - The study aimed to define the role of uncharacterized long noncoding RNAs (lncRNAs) in treatment-naïve ulcerative colitis (UC). Method - To overcome difficulties in lncRNA transcript quantification, multiple and “stringent” strategies were applied. New insights in the regulation of functional genes and pathways of relevance for UC through expression of lncRNAs are expected Conclusion - This study identified a set of 15 yet uncharacterized lncRNAs which may be of importance for UC pathogenesis. These lncRNAs may serve as potential diagnostic biomarkers and might be of use for the development of UC treatment strategies in the future. The proposed method can also be helpful to quantify low expressed lncRNA transcripts in other datasets

Methylation-regulated long non-coding RNA expression in ulcerative colitis

Long non-coding RNAs (lncRNAs) have been shown to play a role in the pathogenesis of ulcerative colitis (UC). Although epigenetic processes such as DNA methylation and lncRNA expression are well studied in UC, the importance of the interplay between the two processes has not yet been fully explored. It is, therefore, believed that interactions between environmental factors and epigenetics contribute to disease development. Mucosal biopsies from 11 treatment-naïve UC patients and 13 normal controls were used in this study. From each individual sample, both whole-genome bisulfite sequencing data (WGBS) and lncRNA expression data were analyzed. Correlation analysis between lncRNA expression and upstream differentially methylated regions (DMRs) was used to identify lncRNAs that might be regulated by DMRs. Furthermore, proximal protein-coding genes associated with DMR-regulated lncRNAs were identified by correlating their expression. The study identified UC-associated lncRNAs such as MIR4435-2HG, ZFAS1, IL6-AS1, and Pvt1, which may be regulated by DMRs. Several genes that are involved in inflammatory immune responses were found downstream of DMR-regulated lncRNAs, including SERPINB1, CCL18, and SLC15A4. The interplay between lncRNA expression regulated by DNA methylation in UC might improve our understanding of UC pathogenesis

Plasma Fatty Acid Ratios Affect Blood Gene Expression Profiles - A Cross-Sectional Study of the Norwegian Women and Cancer Post-Genome Cohort

This paper is part of Karina Standahl Olsen's doctoral thesis, available in Munin at http://hdl.handle.net/10037/5442High blood concentrations of n-6 fatty acids (FAs) relative to n-3 FAs may lead to a “physiological switch” towards permanent low-grade inflammation, potentially influencing the onset of cardiovascular and inflammatory diseases, as well as cancer. To explore the potential effects of FA ratios prior to disease onset, we measured blood gene expression profiles and plasma FA ratios (linoleic acid/alpha-linolenic acid, LA/ALA; arachidonic acid/eicosapentaenoic acid, AA/EPA; and total n-6/n-3) in a cross-section of middle-aged Norwegian women (n = 227). After arranging samples from the highest values to the lowest for all three FA ratios (LA/ALA, AA/EPA and total n-6/n-3), the highest and lowest deciles of samples were compared. Differences in gene expression profiles were assessed by single-gene and pathway-level analyses. The LA/ALA ratio had the largest impact on gene expression profiles, with 135 differentially expressed genes, followed by the total n-6/n-3 ratio (125 genes) and the AA/EPA ratio (72 genes). All FA ratios were associated with genes related to immune processes, with a tendency for increased pro-inflammatory signaling in the highest FA ratio deciles. Lipid metabolism related to peroxisome proliferator-activated receptor γ (PPARγ) signaling was modified, with possible implications for foam cell formation and development of cardiovascular diseases. We identified higher expression levels of several autophagy marker genes, mainly in the lowest LA/ALA decile. This finding may point to the regulation of autophagy as a novel aspect of FA biology which warrants further study. Lastly, all FA ratios were associated with gene sets that included targets of specific microRNAs, and gene sets containing common promoter motifs that did not match any known transcription factors. We conclude that plasma FA ratios are associated with differences in blood gene expression profiles in this free-living population, and that affected genes and pathways may influence the onset and progression of disease

Boundary and volumetric sensitivity kernels of teleseismic receiver functions for mantle discontinuities in the transition zone

Teleseismic receiver functions are widely used to map the depth and topography of various major discontinuities in the Earth's mantle. To determine what precisely contributes to the receiver functions, we applied the adjoint method of full waveform inversion to calculate their sensitivity kernels. These kernels illustrate the extend to which model parameters may influence the waveforms. We calculated synthetic data for a realistic event measured at a realistic receiver array, whereby we focused on the waveforms of the P410s and P660s phases, that convert a P to an S wave at the 410- and 660-discontinuity, respectively. We calculated both the volumetric sensitivity kernels for density, P- and S-wave speeds, as well as boundary kernels that illustrate receiver functions' sensitivity to topography on the discontinuity. In the boundary kernels, we observe that receiver functions are highly sensitive to a discontinuity's topography, in particular to an area surrounding the conversion point with a radius comparable to the Fresnel zone. However, the volumetric kernels illustrate a sensitivity to model parameters in large areas of the mantle. This includes sensitivity to the Fresnel zone of the converted wave far before the conversion, as well as sensitivity to scatterers of other phases. We therefore conclude that receiver functions are sensitive to the topography of discontinuities. However, effects of an incorrect velocity model, even far from the conversion point, may erroneously be projected onto the topography of the discontinuity. Therefore, a simultaneous inversion of topography and velocity parameters is required to image topography with high accuracy

Sensitivity kernels for receiver function misfits in a full waveform inversion workflow

Receiver functions have been used for decades to study the Earth's major discontinuities by focusing on converted waves. Deconvolution, which is the mathematical backbone of the method, is assumed to remove the source time function and the far-field dependence on structure, making it a useful method to map the nearby Earth structure and its discontinuities. Ray theory, a plane incoming wavefield, and a sufficiently well-known near-receiver background velocity model are conventionally assumed to map the observations to locations in the subsurface. Many researchers are aware of the shortcoming of these assumptions and several remedies have been proposed for mitigating their consequences. Adjoint tomography with a quasi-exact forward operator is now within reach for most researchers, and we believe is the way forward in receiver function studies. A first step is to calculate adjoint sensitivity kernels for a given misfit function. Here, we derive the adjoint source for a receiver function waveform misfit. Using a spectral element forward code, we have calculated sensitivity kernels for P-to-S converted waves using several 2-D models representing an average crust with an underlying mantle. The kernels show profound differences between P- and S-wave speed sensitivity. The sensitivity to P-wave speed is wide-ranging and related to the scattered P-wavefield which interferes with that of the P-to-S converted wave. The S-wave speed sensitivity is more local and mostly associated to potential locations of P-to-S conversion, although more distant sensitivity is also observed. Notably, there is virtually no sensitivity to impedance. We further observe the well-known trade-off between depth of the discontinuity and wave speed, but find that considering a longer waveform that includes more surface reverberations reduces this trade-off significantly

Seroprevalence of hepatitis E virus (HEV) in a general adult population in Northern Norway: the Tromsø study

This is a post-peer-review, pre-copyedit version of an article published in Medical Microbiology and Immunology. The final authenticated version is available online at: https://doi.org/10.1007/s00430-019-00599-5. Hepatitis E virus (HEV) is a major cause of acute viral hepatitis in many parts of the world but only a few cases have been diagnosed in Norway. To investigate the HEV exposure rate in a presumed low-risk area, we have conducted a population-based study of anti-HEV IgG seroprevalence in Northern Norway. A total of 1800 serum samples from 900 women and 900 men, age 40–79 years, were randomly selected from the 21,083 participants in the 7th Tromsø Study, representing the 32,591 inhabitants of the Tromsø municipality that were ≥ 40 years. All samples were analyzed by ELISA-1 (recomWell HEV IgG). Samples testing positive or borderline, as well as a 1.5-fold excess of negative samples, were retested by ELISA-2 (DiaPro HEV IgG). If still borderline or a result discordant from ELISA-1, the sample was retested by ELISA-3 (Wantai HEV IgG) and strip-immunoassay (recomLine HEV IgG). Anti-HEV IgG was detected in 205 individuals (11.4%), yielding an estimated seroprevalence of 10.4% in the age-matched population of Tromsø. Using logistic regression analysis followed by multivariable backward elimination analysis, increasing age (OR 1.036 per year; p p < 0.001) were found as potential risk factors, whereas travel abroad or eating of red meat were not. Our results indicate that HEV-infection is common in Northern Norway and suggest that HEV testing should be included in the evaluation of elevated liver enzymes

Profiling the T Cell Receptor Alpha/Delta Locus in Salmonids

In jawed vertebrates, two major T cell populations have been characterized. They are defined as α/β or γ/δ T cells, based on the expressed T cell receptor. Salmonids (family Salmonidae) include two key teleost species for aquaculture, rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar) which constitute important models for fish immunology and important targets for vaccine development. The growing interest to decipher the dynamics of adaptive immune responses against pathogens or vaccines has resulted in recent efforts to sequence the immunoglobulin (IG) or antibodies and T cell receptor (TR) repertoire in these species. In this context, establishing a comprehensive and coherent locus annotation is the fundamental basis for the analysis of high-throughput repertoire sequencing data. We therefore decided to revisit the description and annotation of TRA/TRD locus in Atlantic salmon and two strains of rainbow trout (Swanson and Arlee) using the now available high-quality genome assemblies. Phylogenetic analysis of functional TRA/TRD V genes from these three genomes led to the definition of 25 subgroups shared by both species, some with particular feature. A total of 128 TRAJ genes were identified in Salmo, the majority with a close counterpart in Oncorhynchus. Analysis of expressed TRA repertoire indicates that most TRAV gene subgroups are expressed at mucosal and systemic level. The present work on TRA/TRD locus annotation along with the analysis of TRA repertoire sequencing data show the feasibility and advantages of a common salmonid TRA/TRD nomenclature that allows an accurate annotation and analysis of high-throughput sequencing results, across salmonid T cell subsets

Solute-induced shift of phase transition temperature in Di-saturated PC liposomes: adoption of ripple phase creates osmotic stress

AbstractWe have examined the calorimetric behavior of large liposomes consisting of symmetric saturated chain phosphatidylcholines. Most notably, for systems made in solutions containing solute (e.g., NaCl, glucose, etc.) there was an additional major endotherm just below the main phase transition temperature. The new endotherm was found to represent a population of lipid whose main phase transition was shifted to lower temperature due to an induced osmotic stress across the membrane. Absent for isoosmotic systems, the osmotic stress was created when the liposome internal volume decreased, a consequence of the Lβ′ (gel) to Pβ′ (rippled) phase transition. That is, rippling of the membrane caused vesicle volume to decrease (≥28%) and because the free flow of water outward was restricted by solute, an osmotic gradient was created where none had existed before. The distribution of enthalpy between the new shifted Tm and the expected Tm correlated with the percent of lipid in the outer bilayer and it was concluded that only the outer bilayer sensed the induced stress. Internalized liposome structures were shielded, thus explaining the persistence of the expected Tm in preparations made in solute. The shift in Tm (ΔTm) was discrete and linearly dependent upon lipid chain length for the PC series di-17:0 (ΔTm≈1.4°C) through di-20:0 (ΔTm≈0.6°C), suggesting a structural change (i.e., lipid packing/orientation) was involved. Although freeze-fracture electron microscopy of stressed and unstressed bilayers revealed no differences in ripple periodicity there were differences in surface features and in vesicle shape. The fact that this phenomenon has gone unnoticed for MLVs is probably due to the fact that these systems are known to exclude solute and thus exist under osmotic compression