Transcriptional Regulation and Epigenetics in Cardiovascular Cells: Role of the Mineralocorticoid Receptor

The mineralocorticoid receptor (MR), a ligand-activated transcription factor, plays an important role in the pathophysiology of cardiovascular disease. Epigenetic mechanisms such as DNA methylation or histone modifications in addition to the DNA sequence are decisive regulators of cell type-specific transcriptional activity and gene expression by controlling chromatin accessibility. In this review, we summarise the current knowledge about the impact of MR on gene expression in cardiovascular cells. We discuss studies investigating the interaction of MR with epigenetic mechanisms or other transcription factors and their implications for the cardiovascular system. Finally, we compare mechanisms of transcriptional regulation by MR and other nuclear transcription factors. In conclusion, MR is an important regulator of gene expression in cardiovascular cells. Potential mechanisms of cell type-specific transcriptional regulation by MR include interaction with other transcription factors or co-regulators, tethering and post-translational modifications of the MR. Further studies will be needed to clarify the interplay of MR and epigenetic mechanisms

Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD

Leukotriene and purinergic receptors are involved in the hyperpolarizing effect of glucagon in liver cells

AbstractThe pancreatic hormone glucagon hyperpolarizes the liver cell membrane. In the present study, we investigated the cellular signalling pathway of glucagon-induced hyperpolarization of liver cells by using the conventional microelectrode method. The membrane potential was recorded in superficial liver cells of superfused mouse liver slices. In the presence of the K+ channel blockers tetraethylammonium (TEA, 1 mmol/l) and Ba2+ (BaCl2, 5 mmol/l) and the blocker of the Na+/K+ ATPase, ouabain (1 mmol/l), no glucagon-induced hyperpolarization was observed confirming previous findings. The hyperpolarizing effect of glucagon was abolished by the leukotriene B4 receptor antagonist CP 195543 (0.1 mmol/l) and the purinergic receptor antagonist PPADS (5 μmol/l). ATPγS (10 μmol/l), a non-hydrolyzable ATP analogue, induced a hyperpolarization of the liver cell membrane similar to glucagon. U 73122 (1 μmol/l), a blocker of phospholipase C, prevented both the glucagon- and ATPγS-induced hyperpolarization. These findings suggest that glucagon affects the hepatic membrane potential partly by inducing the formation and release of leukotrienes and release of ATP acting on purinergic receptors of the liver cell membrane

Simplified Paper Format for Detecting HIV Drug Resistance in Clinical Specimens by Oligonucleotide Ligation

Human immunodeficiency virus (HIV) is a chronic infection that can be managed by antiretroviral treatment (ART). However, periods of suboptimal viral suppression during lifelong ART can select for HIV drug resistant (DR) variants. Transmission of drug resistant virus can lessen or abrogate ART efficacy. Therefore, testing of individuals for drug resistance prior to initiation of treatment is recommended to ensure effective ART. Sensitive and inexpensive HIV genotyping methods are needed in low-resource settings where most HIV infections occur. The oligonucleotide ligation assay (OLA) is a sensitive point mutation assay for detection of drug resistance mutations in HIV pol. The current OLA involves four main steps from sample to analysis: (1) lysis and/or nucleic acid extraction, (2) amplification of HIV RNA or DNA, (3) ligation of oligonucleotide probes designed to detect single nucleotide mutations that confer HIV drug resistance, and (4) analysis via oligonucleotide surface capture, denaturation, and detection (CDD). The relative complexity of these steps has limited its adoption in resource-limited laboratories. Here we describe a simplification of the 2.5-hour plate-format CDD to a 45-minute paper-format CDD that eliminates the need for a plate reader. Analysis of mutations at four HIV-1 DR codons (K103N, Y181C, M184V, and G190A) in 26 blood specimens showed a strong correlation of the ratios of mutant signal to total signal between the paper CDD and the plate CDD. The assay described makes the OLA easier to perform in low resource laboratories

Recent Developments of Magnetoresistive Sensors for Industrial Applications

The research and development in the field of magnetoresistive sensors has played an important role in the last few decades. Here, the authors give an introduction to the fundamentals of the anisotropic magnetoresistive (AMR) and the giant magnetoresistive (GMR) effect as well as an overview of various types of sensors in industrial applications. In addition, the authors present their recent work in this field, ranging from sensor systems fabricated on traditional substrate materials like silicon (Si), over new fabrication techniques for magnetoresistive sensors on flexible substrates for special applications, e.g., a flexible write head for component integrated data storage, micro-stamping of sensors on arbitrary surfaces or three dimensional sensing under extreme conditions (restricted mounting space in motor air gap, high temperatures during geothermal drilling).DFG/CRC/653German Federal Ministry of Education and Researc

Outcome of radioiodine therapy for feline hyperthyroidism: Fixed dose versus individualized dose based on a clinical scoring system.

Background Hyperthyroidism is the most frequent endocrinopathy in older cats. To date, there is no consensus on how to best calculate the dose of radioiodine to administer to hyperthyroid cats. Aim The goals of this study were to compare thyroid function, renal function, and survival time between hyperthyroid cats receiving a fixed dose of radioiodine and those receiving an individualized dose calculated using a clinical scoring system. Methods Medical records of 110 cats treated with radioiodine therapy at the University of Bern between 2010 and 2020 were reviewed. Thyroid function, renal function, and survival of cats treated with a fixed dose of radioiodine (2010-2015; n = 50) were compared to those of cats treated with an individualized dose (2015-2020; n = 60) at different time points after therapy. Results Treatment with a fixed dose of radioiodine (mean = 168 ± 26 MBq) was associated with 69% of euthyroidism, 19% persistent hyperthyroidism, and 12% hypothyroidism, whereas treatment with an individualized dose (mean = 120 ± 30 MBq) led to 54% euthyroidism, 23% hyperthyroidism, and 23% hypothyroidism (p = 0.73). More than 12 months after treatment, the incidence of azotemia was comparable between cats treated with a fixed dose (37%) and those treated with an individualized dose (31%) (p = 0.77). No factors were found to be predictive of treatment failure (hypothyroidism or hyperthyroidism) after therapy. Median survival time after radioiodine therapy was 44 months. In a multivariate analysis, persistent hyperthyroidism was the only variable independently associated with a shorter survival time (HR = 6.24, p = 0.002). Conclusion The method of calculating the dose of radioiodine (fixed vs. individualized) to treat feline hyperthyroidism does not appear to be decisive for posttreatment thyroid function, renal function, or survival

LogIKTram: Nachhaltiger straßenbahnbasierter Gütertransport

Zunehmender städtischer und regionaler Güterverkehr belastet die Anwohner, Verkehrsteilnehmer und die Umwelt. Das Projekt LogIKTram verfolgt das Ziel, regionalen Güterverkehr von der Straße auf die Schiene zu verlagern und somit eine Entlastung zu erzielen. Diese Idee soll am Beispiel einer Gütertram in der Region Karlsruhe erprobt werden. Dafür entwickelt die Hochschule Offenburg unter anderem ein Logistikkonzept und ein Planungsmodell. Beides wird in einer IKT-Plattform umgesetzt.Increasing urban and regional freight traffic is a source of concern for local residents, road users and the environment. The LogIKTram project pursues the goal of shifting regional freight traffic from road to rail and thus achieving relief. This idea is to be tested using the example of a cargo tram in the Karlsruhe region. To this end, Offenburg University of Applied Sciences is developing, a logistics concept and a planning model. Both will be implemented in an ICT platform

Conversion of CO2 into organic acids by engineered autotrophic yeast

The increase of CO2 emissions due to human activity is one of the preeminent reasons for the present climate crisis. In addition, considering the increasing demand for renewable resources, the upcycling of CO2 as a feedstock gains an extensive importance to establish CO2-neutral or CO2-negative industrial processes independent of agricultural resources. Here we assess whether synthetic autotrophic Komagataella phaffii (Pichia pastoris) can be used as a platform for value-added chemicals using CO2 as a feedstock by integrating the heterologous genes for lactic and itaconic acid synthesis. 13C labeling experiments proved that the resulting strains are able to produce organic acids via the assimilation of CO2 as a sole carbon source. Further engineering attempts to prevent the lactic acid consumption increased the titers to 600 mg L−1, while balancing the expression of key genes and modifying screening conditions led to 2 g L−1 itaconic acid. Bioreactor cultivations suggest that a fine-tuning on CO2 uptake and oxygen demand of the cells is essential to reach a higher productivity. We believe that through further metabolic and process engineering, the resulting engineered strain can become a promising host for the production of value-added bulk chemicals by microbial assimilation of CO2, to support sustainability of industrial bioprocesses

Combinations of low-frequency genetic variants might predispose to familial pancreatic cancer

Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants