Invasive mould infections: a multi-disciplinary update

Systemic fungal infections remain a significant cause of mortality in neutropenic and immunocompromised patients, despite advances in their diagnosis and treatment. The incidence of such infections is rising due to the use of intensive chemotherapy regimens in patients with solid tumours or haematological cancers, the increasing numbers of allogeneic haematopoietic stem cell and solid organ transplants, and the use of potent immunosuppressive therapy in patients with autoimmune disorders. In addition, the epidemiology of systemic fungal infections is changing, with atypical species such as Aspergillus terreus and zygomycetes becoming more common. Treatment has traditionally focused on empirical therapy, but targeted pre-emptive therapy in high-risk patients and prophylactic antifungal treatment are increasingly being adopted. New treatments, including lipid formulations of amphotericin B, second-generation broad-spectrum azoles, and echinocandins, offer effective antifungal activity with improved tolerability compared with older agents; the potential impact of these treatments is reflected in their inclusion in current treatment and prophylaxis guidelines. New treatment strategies, such as aerosolized lipid formulations of amphotericin B, may also reduce the burden of mortality associated with systemic fungal infections. The challenge is to identify ways of coupling potentially effective treatments with early and reliable identification of patients at highest risk of infectio

Process analytical technologies for a continuous capture and connected downstream process

As we move towards the implementation of continuous and connected processes, it becomes apparent that we can no longer avail ourselves of traditional sampling points (pools). Therefore, the implementation of Process Analytical Technologies (PAT) to demonstrate process robustness or to monitor process consistency, becomes necessary. Methodologies to monitor mass and yield are still necessary and the need to have at- or on-line analytics becomes more real. In-between, it may be necessary to bridge between the traditional analysis of unit pools to a more dynamic process monitoring. Recovered product mass and step yields per unit operation are commonly used to monitor process robustness. This is however more challenging in a connected/continuous mode, where there are no longer pools. The presented approach will demonstrate how UV absorption measurements can be utilized to track yield and to show process consistency. To tackle the issue of signal saturation, variable pathlength measurements as well as UV measurements at 300 nm were used. While univariate UV measurements were used for post-Protein A steps, multivariate measurements in conjunction with Partial Least Squares Regression modelling were evaluated for mass tracking in harvest. The monitoring of quality attributes within continuous processes also requires an adapted approach. The most straightforward approach in this context is the automation of already existing assays. The poster will present how the turnover time of an offline SEC assay was reduced to 1 min and how the method was applied for automated aggregate analysis. Furthermore, it will be shown how an Online-UPLC assay was used to control the aggregate level in chromatography runs with variable column load densities and aggregate levels in the load. Until at- or on-line analytics can be developed for all critical quality attributes, a bridging method is required. Here, a testing strategy based on pseudo-product pools will be presented, which allows bridging of quality data from a continuous process stream to a traditional standard batch pool concept. Slip stream pumps were used to generate pseudo pools, whenever product pools were not available. It was demonstrated, that the pseudo pools are representative and that the data is applicable for statistical comparison with historical batch data.

Institutional path-dependencies in Europe’s networked modes of governance

We consider whether transnational networks that softly discipline member states (e.g. the OMC or regulatory networks that oversee national discretion in implementing broad EU frameworks) mark a significant turn in European integration or merely a transitional step towards centralisation (e.g. agencification) and formalisation (subjecting to law). We suggest this requires a closer reading of the institutional changes necessary to bring about centralisation/formalisation, and ask particularly whether change might be partially attributable to the very institutional-agents operating inside Europe’s networked modes of governance. Supplementing functional-political explanations, we propose an endogenous model of institutional change that incorporates the independent role transnational networks play in shaping their own institutionalisation, which may make this mode of governance more resilient and even self-reinforcing. We test the plausibility of this model with a case study detailing the institutional entrepreneurship of transnational networks in the telecoms sector

Atomic mutagenesis of stop codon nucleotides reveals the chemical prerequisites for release factor-mediated peptide release.

Termination of protein synthesis is triggered by the recognition of a stop codon at the ribosomal A site and is mediated by class I release factors (RFs). Whereas in bacteria, RF1 and RF2 promote termination at UAA/UAG and UAA/UGA stop codons, respectively, eukaryotes only depend on one RF (eRF1) to initiate peptide release at all three stop codons. Based on several structural as well as biochemical studies, interactions between mRNA, tRNA, and rRNA have been proposed to be required for stop codon recognition. In this study, the influence of these interactions was investigated by using chemically modified stop codons. Single functional groups within stop codon nucleotides were substituted to weaken or completely eliminate specific interactions between the respective mRNA and RFs. Our findings provide detailed insight into the recognition mode of bacterial and eukaryotic RFs, thereby revealing the chemical groups of nucleotides that define the identity of stop codons and provide the means to discriminate against noncognate stop codons or UGG sense codons