Bistable switches are fundamental regulatory elements of complex systems, ranging from electronics to living cells. Designed genetic toggle switches have been constructed from pairs of natural transcriptional repressors wired to inhibit one another. The complexity of the engineered regulatory circuits can be increased using orthogonal transcriptional regulators based on designed DNA-binding domains. However, a mutual repressor-based toggle switch comprising DNA-binding domains of transcription-activator-like effectors (TALEs) did not support bistability in mammalian cells. Here, the challenge of engineering a bistable switch based on monomeric DNA-binding domains is solved via the introduction of a positive feedback loop composed of activators based on the same TALE domains as their opposing repressors and competition for the same DNA operator site. This design introduces nonlinearity and results in epigenetic bistability. This principle could be used to employ other monomeric DNA-binding domains such as CRISPR for applications ranging from reprogramming cells to building digital biological memory.

Fibrosis is an important feature of inflammatory bowel diseases (IBD), but its pathogenesis is incompletely understood. Our aim was to identify genes important for fibrosis in IBD by comparison with kidney and liver fibrosis. First, we performed bioinformatics analysis of Gene Expression Omnibus datasets of liver and kidney fibrosis and identified CXCL9, THBS2, MGP, PTPRC, CD52, GZMA, DPT and DCN as potentially important genes with altered expression in fibrosis. We then performed qPCR analysis of the selected genes’ expression on samples of fibrotic kidney, liver, Crohn’s disease (CD) with and without fibrosis and ulcerative colitis (UC), in comparison to corresponding normal tissue. We found significantly altered expression in fibrosis for all selected genes. A significant difference for some genes was observed in CD with fibrosis in comparison to CD without fibrosis and UC. We conclude that similar changes in the expression of selected genes in liver, kidney fibrosis and IBD provide further evidence that fibrosis in IBD might share common mechanisms with other organs, supporting the hypothesis that fibrosis is the common pathway in diseases of various organs. Some genes were already active in IBD with inflammation without fibrosis, suggesting the early activation of profibrotic pathways or overlapping function in fibrosis and inflammation.

The number of published cases of presumed iatrogenic cerebral amyloid angiopathy (iCAA) due to the transmission of amyloid β during neurosurgery is slowly rising. One of the potential ways of transmission is through a cadaveric dura mater graft (LYODURA) exposure during neurosurgery. This is a case of a 46-year-old female patient with no chronic conditions who presented with recurrent intracerebral haemorrhages (ICHs) without underlying vessel pathology. Four decades prior, the patient had a neurosurgical procedure with documented LYODURA transplantation. Brain biopsy confirmed CAA. This is a rare case of histologically proven iCAA after a documented LYODURA transplantation in childhood. Our case and already published iCAA cases emphasize the need for considering neurosurgery procedure history as important data in patients who present with ICH possibly related to CAA.

Ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by an imbalance between pro-inflammatory and anti-inflammatory cytokines, interfering with the resolution of inflammation. Due to the crucial role of cytokines, new insights into their profiles in UC and CD would help to improve our understanding of pathogenesis and enable the development of new treatment modalities. We provide an expression profile of cytokines in UC and CD, using bioinformatics approach, and experimental validation of expression of the selected genes. We retrieved data and analyzed the cytokine gene expression profiles of UC and CD. From ten genes with inverse expression, common to CD and UC, BMP8B, LEFTY1 and INSL5 were selected for gene expression experimental validation. Experimentally, BMP8B and INSL5 were down-regulated in both CD and UC but followed the bioinformatics trend. The expression of genes LEFTY1 and BMP8B was statistically significant when comparing UC and CD in colon and the expression of gene LEFTY1 showed statistical significance when CD in ileum and colon were compared. Using the bioinformatics approach and experimental validation, we found differences in expression profiles between UC and CD for INSL5, LEFTY1 and BMP8B. These three promising candidate genes need to be further explored at different levels, such as DNA methylation and protein expression, to provide more evidence on their potential diagnostic role in CD and UC.

Crohn’s disease (CD) is frequently complicated by strictures that can be either inflammatory or fibrostenotic. This distinction is important for deciding the best treatment course, but it can be difficult to determine clinically, sometimes even by advanced imaging techniques. We performed miRNA PCR panel screening on pooled samples of ileum with CD fibrostenosis or inflammatory stenosis. Eight miRNAs with profibrotic (miR-93-5p, miR-376c-3p and miR-424-5p), or fibroprotective (miR-133a-3p, miR-133b, miR-193a-5p, miR-335-5p and miR-378a-3p) functions described in the literature were selected for validation on 20 samples each of CD with fibrostenosis or inflammatory stenosis, with a separate sampling of the submucosa and subserosa. The results showed significant differences between the groups in subserosal samples, with upregulation of profibrotic miRNAs and downregulation of fibroprotective miRNAs in fibrostenosis compared to inflammatory stenosis. Only miR-424-5p showed a significant difference in the submucosa. There were significant differences in miRNA expression between subserosa and submucosa. Our results provide further evidence that the major differences between fibrostenosis and inflammatory stenosis are located in the subserosa, which is inaccessible to endoscopic sampling, highlighting the need for cross-sectional imaging or serological markers. We identify several miRNAs previously not connected to fibrosis in CD, which could potentially serve as biomarkers of fibrostenosis.