“Holistic Risk-based Site Surveillance – A Data-based Approach to Site Quality Risk Identification and Assessment in the Pharmaceutical Industry”

Effective quality risk management is fundamental in guaranteeing the development and manufacture of high-quality drugs, reducing drug shortages, and avoiding harm to patients’ health. The ability to accurately assess the actual risk environment, predict potential product quality or supply disruption issues and act to eliminate, prevent, reduce or mitigate them is key to improvements in quality management maturity. This paper illustrates a just-launched research project aimed at developing a comprehensive framework for how to assess and predict risks by leveraging a range of diverse factors

A Holistic View on Production Systems Management

Almost every large corporation nowadays operates some sort of Production System (PS), usually built as a derivative from leading examples like the Toyota Production System. Production Systems (PSs) are introduced to increase operational performance and to eventually instill a culture of continuous improvement across the mostly globally dispersed production networks. The main question is not any longer if PSs are helpful but how to manage them. So far there is neither an answer to this question in practice nor in literature. That is, how to design and develop the content, the process and the organizational support structure of a PS, and thus providing a corporate perspective to managing PSs, is heavily under researched. The methodological approach in this paper is twofold. First, a systematic literature review was conducted to identify appropriate papers dealing with this topic. Second, we draw on interviews with corporate representatives being accountable for the PS at 11 respective companies from the Pharmaceutical industry. The companies have been selected based on their maturity of production system implementation. Interviews were transcribed and coded. We found various activities related to the three dimensions of content, process, and structure of PSs. Thereby, we provide an overview of activities for managing PSs. We add to the literature of PSs from a corporate perspective and derive several future research opportunities, such as if there are multiple ways in combining the identified activities to be successful with a PS. Our limitation is that interviewees are from the pharmaceutical industry only, yet the level of sophistication of PSs in this industry and the twofold approach mitigate the limitation

Southern Ocean bottom-water cooling and ice sheet expansion during the middle Miocene climate transition

The middle Miocene climate transition (MMCT), around 14 Ma, was associated with a significant climatic shift, but the mechanisms triggering the event remain enigmatic. We present a clumped isotope (Δ47) bottom-water temperature (BWT) record from 16.0 to 12.2 Ma from Ocean Drilling Program (ODP) Site 747 in the Southern Ocean and compare it to existing BWT records from different latitudes. We show that BWTs in the Southern Ocean reached 8–10 ∘C during the Miocene climatic optimum. These high BWT values indicate considerably warmer bottom-water conditions than today. Nonetheless, bottom-water δ18O (calculated from foraminiferal δ18O and Δ47) suggests substantial amounts of land ice throughout the interval of the study. Our dataset further demonstrates that BWTs at Site 747 were variable with an overall cooling trend across the MMCT. Notably, a cooling of around 3–5 ∘C preceded the stepped main increase in benthic δ18O, interpreted as global ice volume expansion, and appears to have been followed by a transient bottom-water warming starting during or slightly after the main ice volume increase. We speculate that a regional freshening of the upper water column at this time may have increased stratification and reduced bottom-water heat loss to the atmosphere, counteracting global cooling in the bottom waters of the Southern Ocean and possibly even at larger scales. Feedbacks required for substantial ice growth and/or tectonic processes may have contributed to the observed decoupling of global ice volume and Southern Ocean BWT.publishedVersio

Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin

Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down contro

Cyclosporine A-Sensitive, Cyclophilin B-Dependent Endoplasmic Reticulum-Associated Degradation

Peptidyl-prolyl cis/trans isomerases (PPIs) catalyze cis/trans isomerization of peptide bonds preceding proline residues. The involvement of PPI family members in protein refolding has been established in test tube experiments. Surprisingly, however, no data is available on the involvement of endoplasmic reticulum (ER)-resident members of the PPI family in protein folding, quality control or disposal in the living cell. Here we report that the immunosuppressive drug cyclosporine A (CsA) selectively inhibits the degradation of a subset of misfolded proteins generated in the ER. We identify cyclophilin B (CyPB) as the ER-resident target of CsA that catalytically enhances disposal from the ER of ERAD-LS substrates containing cis proline residues. Our manuscript presents the first evidence for enzymatic involvement of a PPI in protein quality control in the ER of living cells

Efficiency of monolaurin in mitigating ruminal methanogenesis and modifying C-isotope fractionation when incubating diets composed of either C3 or C4 plants in a rumen simulation technique (Rusitec) system

Mitigation of methanogenesis in ruminants has been an important goal for several decades. Free lauric acid, known to suppress ruminal methanogenesis, has a low palatability; therefore, in the present study the aim was to evaluate the mitigation efficacy of its esterified form (monolaurin). Further, 13C-isotope abundance (δ13C) and 13C-12C fractionation during methanogenesis and fermentation were determined to evaluate possible microbial C-isotope preferences. Using the rumen simulation technique, four basal diets, characterised either by the C3 plants grass (hay) and wheat (straw and grain), or the C4 plant (13C excess compared with C3 plants) maize (straw and grain), and a mixture of the latter two, were incubated with and without monolaurin (50g/kg dietary DM). Added to hay, monolaurin did not significantly affect methanogenesis. When added to the other diets (P<0·05 for the wheat-based diet) methane formation was lowered. Monolaurin decreased fibre disappearance (least effect with the hay diet), acetate:propionate ratio, and protozoal counts. Feed residues and SCFA showed the same δ13C as the diets. Methane was depleted in 13C while CO2 was enriched in 13C compared with the diets. Monolaurin addition resulted in 13C depletion of CO2 and enrichment in CH4 (the latter only in the hay diet). In conclusion, monolaurin proved to effectively decrease methanogenesis in the straw-grain diets although this effect might partly be explained by the concomitantly reduced fibre disappearance. The influence on 13C-isotope abundance and fractionation supports the hypothesis that ruminal microbes seem to differentiate to some extent between C-isotopes during methanogenesis and fermentatio