Novel ZNF414 activity characterized by integrative analysis of ChIP-exo, ATAC-seq and RNA-seq data

Transcription factor binding to DNA is a central mechanism regulating gene expression. Thus, thorough characterization of this process is essential for understanding cellular biology in both health and disease. We combined data from three sequencing-based methods to unravel the DNA binding function of the novel ZNF414 protein in cells representing two tumor types. ChIP-exo served to map protein binding sites, ATAC-seq allowed identification of open chromatin, and RNA-seq examined the transcriptome. We show that ZNF414 is a DNAbinding protein that both induces and represses gene expression. This transcriptional response has an impact on cellular processes related to proliferation and other malignancy-associated functions, such as cell migration and DNA repair. Approximately 20% of the differentially expressed genes harbored ZNF414 binding sites in their promoters in accessible chromatin, likely representing direct targets of ZNF414. De novo motif discovery revealed several putative ZNF414 binding sequences, one of which was validated using EMSA. In conclusion, this study illustrates a highly efficient integrative approach for the characterization of the DNA binding and transcriptional activity of transcription factors.Peer reviewe

Dissecting the contribution of single nucleotide polymorphisms in CCR9 and CCL25 genomic regions to the celiac disease phenotype

Purpose and objectives: Given their role in homing immune cells to the intestine, CC motif chemokine receptor 9 (CCR9) and its specific ligand CC motif chemokine ligand 25 (CCL25) are interesting candidate genes for celiac disease. These genes are located in regions previously shown to be associated with or linked to celiac disease, but no investigations on their association with various celiac disease phenotypes have so far been conducted. Here we studied such associations of both genotyped and imputed single nucleotide polymorphisms (SNPs) with either regulatory function or exonic location of the CCR9 and CCL25 loci. Results: Exploiting a carefully phenotyped cohort of 625 celiac disease patients and 1817 non-celiac controls, we identified that multiple SNPs with predicted regulatory function (RegulomeDB score 0.05). Conclusions: We conclude that SNPs in the region of CCR9 and CCL25 with predicted functional effect or exonic localization likely contribute only modestly to various celiac disease phenotypes.Peer reviewe

Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (P-T) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (P-EMP2 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (P-T = 0.2, P-EMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.Peer reviewe

Logic Filters

Being a two valued logics, classical logic associates with each proposition one of the two values: true or false. In contrast to the classical logics a non-classical many-valued logics was introduced. In many valued logics any proposition could have many values for the truth, from total false to complete truth. Mathematicians Adolf Lindenbaum (1904-1941) and Alfred Tarski (1901-1983) investigated an approach for establishing correspondence between logic and an algebraic structure. First logic for which such a correspondence has been established was a Boolean algebra that models the classical logic. Similarly, BL-algebras are algebraic structures associated with basic fuzzy logic. MV-algebras in turn rise as Lindenbaum algebras from the Łukasiewicz logic, G-algebras rise from Gödel logic and eventually, product algebras rise from the product logic. The notion of the construction of the Lindenbaum-Tarski algebra is related to the factoring the algebra with the congruence relation. Based on this idea we can derive a quotient algebra for the particular algebraic structure. In our thesis we study quotient algebras generated by the logic filters and deductive systems. Additionally, we study different types of filters, their properties and conditions under which they correspond to each other. We describe filters, implicative filters, deductive systems and their properties. Next we observe quotient algebras generated by the filters and deductive systems

Composition, Technological, and Microstructural Aspects of Concrete Modified with Finely Ground Mussel Shell Powder

Reducing the negative environmental impact of a widely spread building material such as concrete is possible by decreasing the amount of cement in this composite material, especially when specific waste is included as a substitution for the binder. Another important environmental issue is accumulated aquaculture waste. This work justifies the possibility of achieving modified concrete with improved properties based on sea mussel shell powder (MSP). An improved environmentally friendly concrete was obtained and modified with MSP as a result of experimental studies. The dosage of MSP in the amount of 6% instead of part of the cement turned out to be optimal and most effective. Because of the modification, it was possible to increase the strength properties: the increments were up to 12% for the compressive strength (CS), up to 13% for the axial CS, up to 14% for the tensile strength (TS) in bending, and up to 12% for the axial TS. The ultimate strains under axial compression and tension decreased to 9% and 12%, respectively, and the elastic modulus increased to 15%. SEM analysis showed a more integral microstructure without voids and cracks in this composite with a modifier content of 6% compared with the sample of the ordinary composition. Economic efficiency is expressed in reducing the total cost of new concrete compared to traditional ones by about 17% and the cost of building construction by up to 15% due to a decrease in the percentage of defects

Improved Fly Ash Based Structural Foam Concrete with Polypropylene Fiber

The direction of construction science that is associated with the development of the theory and practice of creating a new generation of foam concrete is particularly interesting and relevant. The development of improved structural foam concrete using polypropylene fiber and industrial waste, namely fly ash (FA), is prompted by the existing environmental threat posed by FA; this threat is a result of the operation of the fuel energy industry, as well as the possibility of using foam concrete not only as thermal insulation, but as the main material for load-bearing structures that have a certain level of responsibility. The aim of this work was to create and optimize the recipe technological parameters to produce non-autoclaved fiber foam concrete (FFC) using FA as a component. The study used standardized methods for assessing the properties of FFC, and the method of optical microscopy to analyze the structural characteristics of the material. It has been revealed that the replacement of cement with FA in an amount of 10% to 40% helps to reduce the dry density (DD) of FFC. The lowest DD was recorded for samples with 40% FA. The best results for the compressive strength (CS) and flexural strength (FS) were recorded for FFC samples with 10% FA instead of cement. The increase in CS was 12%, and the increase in FS was 23%. The best thermal insulation properties of FFC, and in terms of resistance to freezing and thawing, were recorded in samples with a 10% replacement of cement with FA. The maximum decrease in thermal conductivity was 14%

Influence of Variotropy on the Change in Concrete Strength under the Impact of Wet–Dry Cycles

One of the most dangerous types of cyclic effects, especially inherent in several regions in the world, is the alternating impact of wetting and drying on concrete and reinforced concrete structures. In the current scientific literature and practice, there is not enough fundamental and applied information about the resistance to wetting and drying of variotropic concretes obtained by centrifugal compaction methods. The purpose of the study was to investigate the effect of various technological, compositional, and other factors on the final resistance of variotropic concrete to alternating cycles of moistening and drying. For this, special methods for testing concrete samples were used in the work. It has been established that after strength gain as a result of hydration, there is a tendency for strength loss due to concrete wear. An acidic medium has the most negative effect on the strength characteristics of concretes made using various technologies, compared with neutral and alkaline media. The loss of strength of concrete when moistened in an acidic medium was greater than in alkaline and especially neutral media. The vibrocentrifuged concrete turned out to be the most resistant to the impact of an aggressive environment and the cycles of moistening and drying, compared to the centrifuged and vibrated concrete. The drop in strength was up to 7% less compared to centrifuged concrete and up to 17% less than vibrated concrete

Influence of Variotropy on the Change in Concrete Strength under the Impact of Wet–Dry Cycles

One of the most dangerous types of cyclic effects, especially inherent in several regions in the world, is the alternating impact of wetting and drying on concrete and reinforced concrete structures. In the current scientific literature and practice, there is not enough fundamental and applied information about the resistance to wetting and drying of variotropic concretes obtained by centrifugal compaction methods. The purpose of the study was to investigate the effect of various technological, compositional, and other factors on the final resistance of variotropic concrete to alternating cycles of moistening and drying. For this, special methods for testing concrete samples were used in the work. It has been established that after strength gain as a result of hydration, there is a tendency for strength loss due to concrete wear. An acidic medium has the most negative effect on the strength characteristics of concretes made using various technologies, compared with neutral and alkaline media. The loss of strength of concrete when moistened in an acidic medium was greater than in alkaline and especially neutral media. The vibrocentrifuged concrete turned out to be the most resistant to the impact of an aggressive environment and the cycles of moistening and drying, compared to the centrifuged and vibrated concrete. The drop in strength was up to 7% less compared to centrifuged concrete and up to 17% less than vibrated concrete

The role of polygenic risk and susceptibility genes in breast cancer over the course of life

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10–90th percentile) have a lifetime risk of breast cancer at 55% (95% CI 49–61%), which increases to 84% (71–97%) with a high PRS (> 90th percentile), and decreases to 49% (30–68%) with a low PRS (< 10th percentile). Similarly, for c.1100delC in CHEK2 (3.7–fold enrichment; 1648 carriers), the respective lifetime risks are 29% (27–32%), 59% (52–66%), and 9% (5–14%). The PRS also refines the risk assessment of women with first-degree relatives diagnosed with breast cancer, particularly among women with positive family history of early-onset breast cancer. Here we demonstrate the opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.publishedVersionPeer reviewe