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MicroRNAs (miRNAs) play an important role in the regulation of gene expression. The binding to target messenger RNAs (mRNAs) results in mRNA cleavage or inhibition of the translational machinery leading to decreased protein levels. Various signalling pathways, including apoptosis are modulated by miRNAs. Here, we investigated the role of miR-744-5p in apoptosis signalling in ovarian cancer cell lines. MiR-744-5p expression was reduced in the cancer cell lines independent of the host gene MAP2K4. Overexpression of miR-744-5p activated the intrinsic apoptotic pathway in SKOV3, OVCAR3 and Cisplatin resistant (A2780-cis) and non-resistant A2780 cells leading to cell death. Notably, miR-744-5p overexpression together with Carboplatin treatment led to at least additive pro-apoptotic effects. Investigation of the apoptotic signalling pathways mediated by miR-744-5p revealed that its elevated expression directly downregulated mRNA and protein expression of nuclear factor I X (NFIX) and heterogeneous nuclear ribonucleoprotein C (HNRNPC). HNRNPC caused diminished miR-21 expression and AKT phosphorylation, while NFIX decreased Bcl2 levels, leading to the detected pro-apoptotic effects. Finally, Kaplan-Meier-Plots showed a prolonged median disease-free survival in ovarian serous cystadenocarcinoma patients with high miR-744 expression.

Human activity over the past century has greatly disrupted the natural nitrogen (N) balance, harming health and the environment. Sustainable nitrogen management requires cross-sectoral governance, but studies tracking nitrogen flows across sectors are limited. This study assesses cross-sectoral sources, flows, and sinks of reactive nitrogen (Nr) in Austria, identifying direct Nr inputs and emitting sectors. Using the ‘UNECE-Guidance Document on National Nitrogen Budgets’ and material flow analysis, we quantified Austria’s national nitrogen budget for 2015–2019. Results show the main nitrogen inflows and outflows from imports and exports in the consumer goods and chemical industries. Energy imports also contribute significantly. Some nitrogen is temporarily stored (e.g. in products) or transferred between sectors. However, not all of this N-loss is of direct environmental concern. Annually, 389 kt Nr are lost directly to the environment and causing significant environmental and economic consequences. Direct Nr inputs primarily originate from agriculture (39.3%) and energy/transport (20.7%), with around 30% from cross-border fluxes via water (13.9%) and air (16.6%). The remaining 10% stem from settlements, waste management, and industry. This study highlights the complexity of nitrogen sources and sinks in Austria and underscores the need for improvements towards reduced uncertainties in future research, including higher-resolution spatial data to account for regional variability.

(1) Background: Genetically based hyperinflammation may play a role in pathogen defense. We here questioned whether alterations in circulating monocytes/macrophages, inflammatory biomarkers and a functional SNP (single nucleotide polymorphisms) of the Interleukin-6 (IL-6) promotor might play a role in patients with persistent, and treatment resistant borreliosis. (2) Methods: Leukocyte subpopulations were studied by flow cytometry; plasma cytokines were determined by a chemiluminescence based ELISA (Immulite®), and genotypes of the IL-6 promotor SNP rs1800795 were determined by pyrosequencing. (3) Results: In a cohort of n = 107 Lyme borreliosis patients, who concomitantly manifested either malignant diseases (group 1), autoimmune disorders (group 2), neurological diseases (group 3), or morbidities caused by multiple other infectious complications (group 4), we found decreased numbers of anti-inflammatory CD163-positive macrophages, elevated concentrations of inflammatory cytokines, and an imbalance of IL-6 promotor SNP rs1800795 genotypes. The most prominently upregulated cytokines were IL-1β, and IL-8. (4) Conclusions: Increased pro-inflammatory phenotypes identified by monocyte/macrophage subtypes and concomitantly increased cytokines appear to be valid to monitor disease activity in patients with persistent Lyme borreliosis. Patterns may vary by additional co-morbidities. In patients with autoimmune diseases, increased frequencies of a heterozygous IL-6 promotor SNP rs1800795 were identified. This functional SNP may guide chronic inflammation, impacting other cytokines to trigger trigger chronicity and therapeutic resistance in Lyme borreliosis.

Mountain hazard risk analysis for transport infrastructure is regularly based on deterministic approaches. Standard risk assessment approaches for roads need a variety of variables and data for risk computation, however without considering potential uncertainty in the input data. Consequently, input data needed for risk assessment are normally processed as discrete mean values without scatter or as an individual deterministic value from expert judgement if no statistical data are available. To overcome this gap, we used a probabilistic approach to analyse the effect of input data uncertainty on the results, taking a mountain road in the Eastern European Alps as a case study. The uncertainty of the input data are expressed with potential bandwidths using two different distribution functions. The risk assessment included risk for persons, property risk and risk for non-operational availability exposed to a multi-hazard environment (torrent processes, snow avalanches and rockfall). The study focuses on the epistemic uncertainty of the risk terms (exposure situations, vulnerability factors and monetary values), ignoring potential sources of variation in the hazard analysis. As a result, reliable quantiles of the calculated probability density distributions attributed to the aggregated road risk due to the impact of multiple mountain hazards were compared to the deterministic outcome from the standard guidelines on road safety. The results based on our case study demonstrate that with common deterministic approaches risk might be underestimated in comparison to a probabilistic risk modelling setup, mainly due to epistemic uncertainties of the input data. The study provides added value to further develop standardized road safety guidelines and may therefore be of particular importance for road authorities and political decision-makers.

Apoptosis is a form of directed programmed cell death with a tightly regulated signalling cascade for the destruction of single cells. MicroRNAs (miRNAs) play an important role as fine tuners in the regulation of apoptotic processes. MiR-493-3p mimic transfection leads to the induction of apoptosis causing the breakdown of mitochondrial membrane potential and the activation of Caspases resulting in the fragmentation of DNA in several ovarian carcinoma cell lines. Ovarian cancer shows with its pronounced heterogeneity a very high death-to-incidence ratio. A target gene analysis for miR-493-3p was performed for the investigation of underlying molecular mechanisms involved in apoptosis signalling pathways. Elevated miR-493-3p levels downregulated the mRNA and protein expression levels of Serine/Threonine Kinase 38 Like (STK38L), High Mobility Group AT-Hook 2 (HMGA2) and AKT Serine/Threonine Kinase 2 (AKT2) by direct binding as demonstrated by luciferase reporter assays. Notably, the protein expression of RAF1 Proto-Oncogene, Serine/Threonine Kinase (RAF1) was almost completely downregulated by miR-493-3p. This interaction, however, was indirect and regulated by STK38L phosphorylation. In addition, RAF1 transcription was diminished as a result of reduced transcription of ETS proto-oncogene 1 (ETS1), another direct target of miR-493-3p. Taken together, our observations have uncovered the apoptosis inducing potential of miR-493-3p through its regulation of multiple target genes participating in the extrinsic and intrinsic apoptosis pathway.

Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in TP53, FGFR3, TP53, ERCC2, PIK3CA, PTEN and STAG2. We reviewed and analyzed the clinical and histological data of 45 patients with a consensus diagnosis of PUN-LMP (n = 8), non-invasive LG-PUC (n = 23), and HG-PUC (n = 14). The proliferation index and mitotic count assessed with MIB-1 and P-HH3 staining, respectively correlated with grading and clinical behavior. Targeted sequencing confirmed frequent FGFR3 mutations in non-invasive papillary tumors and identified mutations in TP53 as high-risk. Cluster analysis of the different immunohistochemical and molecular parameters allowed a clear separation in two different clusters: cluster 1 corresponding to PUN-LMP and LG-PUC (low MIB-1 and mitotic count/FGFR3 and STAG2 mutations) and cluster 2, HG-PUC (high MIB-1 and mitosis count/CK20 +++ expression, FGFR3 WT and TP53 mutation). Further analysis is required to validate and analyze the reproducibility of these clusters and their biological and clinical implication.

Purpose Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival. Methods We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations. Results High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival. Conclusion Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.

References for best cost estimating practices include \"Project Management Body of Knowledge\" Chapter 7, \"Project Cost Management\" (PMI,20Q4), State Agency guideline documents such as Washington State Department of Transportation's (WSDOT) \"Cost Estimating Manual for WSDOT Projects\" (WSDOT. 2009) and the Association for the Advancement of Cost Engineering International (AACEI) Guidelines (AACEI, 2003 et seq.). The deterministic base cost approach process is commonly used by contractors to create a bid price.\\n If the owner uses a more detailed probabilistic costrisk estimating process in the planning and design phases, and includes a reasonably complete risk register in the specifications, two benefits are possible: * The owner's budget for the project will be more likely to reflect a more realistic project cost, leading to a more realistic establishment of an appropriate budget (Fig. 4).This permits sufficient resources to be committed to deal with issues in construction.

This paper analyzes the stability and the welfare properties of R&D cooperations in an oligopolistic market with n firms. It is shown that the sizes of stable coalitions vary significantly with the kind and the actual value of spillovers, the institutional arrangement of cooperation between the firms and the underlying stability concept. Moreover, the welfare maximizing coalition is rarely a stable equilibrium outcome, hence there is scope for political intervention. However, the informational requirements on part of the policy makers are high, and they are at risk to adopt inappropriate measures that are detrimental to social welfare.

This paper analyzes the stability and the welfare properties of R&D cooperations in an oligopolistic market with n firms. It is shown that the sizes of stable coalitions vary significantly with the kind and the actual value of spillovers, the institutional arrangement of cooperation between the firms and the underlying stability concept. Moreover, the welfare maximizing coalition is rarely a stable equilibrium outcome, hence there is scope for political intervention. However, the informational requirements on part of the policy makers are high, and they are at risk to adopt inappropriate measures that are detrimental to social welfare.