Life cycle assessment and cost evaluation of emerging technologies at early stages: The case of continuous flow synthesis of Rufinamide

In the pharma and fine chemical industries, the development of continuous flow technologies is a process intensification step of primary importance towards the manufacturing of high‐quality products, while reducing the environmental impact and cost of production. The sustainability and profitability of a process can be measured through life cycle Assessment and cost evaluation. However, when applied to emerging technologies, these need to be performed at different stages of the process development in order to limit the uncertainties arising from the scale‐up, and hence providing high‐fidelity projections of environmental impacts and costs at larger scales. The output of the assessment can in fact vary significantly depending on the maturity of the technology and this translates into having different results at commercial scale compared to early estimations. Therefore, in this article, we perform an assessment at two different scales of production, lab and mini‐pilot scale, with the aim of quantifying the uncertainties of the assessment related to the scale‐up, identifying the hotspots of the system, and hence providing guidelines for the further steps of process development. The subject of the assessment is the continuous flow synthesis of Rufinamide. It is the first time that this synthesis is evaluated at pilot‐scale. The results show that low yields in the cycloaddition drastically affect the waste management and the production of precursors, and hence increases environmental impacts and cost of production. This calls for the need of prioritizing the optimization of this synthesis step in order to deploy a green and economically competitive production technology

The role of mechanotransduction versus hypoxia during simulated orthodontic compressive strain—an in vitro study of human periodontal ligament fibroblasts

During orthodontic tooth movement (OTM) mechanical forces trigger pseudo-inflammatory, osteoclastogenic and remodelling processes in the periodontal ligament (PDL) that are mediated by PDL fibroblasts via the expression of various signalling molecules. Thus far, it is unknown whether these processes are mainly induced by mechanical cellular deformation (mechanotransduction) or by concomitant hypoxic conditions via the compression of periodontal blood vessels. Human primary PDL fibroblasts were randomly seeded in conventional six-well cell culture plates with O-2-impermeable polystyrene membranes and in special plates with gas-permeable membranes (Lumox (R), Sarstedt), enabling the experimental separation of mechanotransducive and hypoxic effects that occur concomitantly during OTM. To simulate physiological orthodontic compressive forces, PDL fibroblasts were stimulated mechanically at 2 g.cm(-2) for 48 h after 24 h of pre-incubation. We quantified the cell viability by MTT assay, gene expression by quantitative real-time polymerase chain reaction (RT-qPCR) and protein expression by western blot/enzyme-linked immunosorbent assays (ELISA). In addition, PDL-fibroblast-mediated osteoclastogenesis (TRAP(+) cells) was measured in a 72-h coculture with RAW264.7 cells. The expression of HIF-1 alpha, COX-2, PGE2, VEGF, COL1A2, collagen and ALPL, and the RANKL/OPG ratios at the mRNA/protein levels during PDL-fibroblast-mediated osteoclastogenesis were significantly elevated by mechanical loading irrespective of the oxygen supply, whereas hypoxic conditions had no significant additional effects. The cellular-molecular mediation of OTM by PDL fibroblasts via the expression of various signalling molecules is expected to be predominantly controlled by the application of force (mechanotransduction), whereas hypoxic effects seem to play only a minor role. In the context of OTM, the hypoxic marker HIF-1 alpha does not appear to be primarily stabilized by a reduced O-2 supply but is rather stabilised mechanically

Orthodontic bonding to silicate ceramics: impact of different pretreatment methods on shear bond strength between ceramic restorations and ceramic brackets

Objective The study aims to investigate the shear bond strength (SBS) between silicate ceramic restorations and ceramic brackets after different pretreatments and aging methods. Material and methods Leucite (LEU) and lithium disilicate (LiSi) specimens were pretreated with (i) 4% hydrofluoric acid + silane (HF), (ii) Monobond Etch&Prime (MEP), (iii) silicatization + silane (CoJet), and (iv) SiC grinder + silane (SiC). Molars etched (phosphoric acid) and conditioned acted as comparison group. SBS was measured after 24 h (distilled water, 37 °C), 500 × thermocycling (5/55 °C), and 90 days (distilled water, 37 °C). Data was analyzed using Shapiro–Wilk, Kruskal–Wallis with Dunn’s post hoc test and Bonferroni correction, Mann–Whitney U, and Chi2 test (p < 0.05). The adhesive remnant index (ARI) was determined. Results LEU pretreated with MEP showed lower SBS than pretreated with HF, CoJet, or SiC. LiSi pretreated with MEP resulted in lower initial SBS than pretreated with HF or SiC. After thermocycling, pretreatment using MEP led to lower SBS than with CoJet. Within LiSi group, after 90 days, the pretreatment using SiC resulted in lowest SBS values. After HF and MEP pretreatment, LEU showed lower initial SBS than LiSi. After 90 days of water storage, within specimens pretreated using CoJet or SiC showed LEU higher SBS than LiSi. Enamel presented higher or comparable SBS values to LEU and LiSi. With exception of MEP pretreatment, ARI 3 was predominantly observed, regardless the substrate, pretreatment, and aging level. Conclusions MEP pretreatment presented the lowest SBS values, regardless the silicate ceramic and aging level. Further research is necessary. Clinical relevance There is no need for intraoral application of HF for orthodontic treatment

Anterior Open Bite Malocclusion: From Clinical Treatment Strategies towards the Dissection of the Genetic Bases of the Disease Using Human and Collaborative Cross Mice Cohorts

Anterior open bite malocclusion is a complex dental condition characterized by a lack of contact or overlap between the upper and lower front teeth. It can lead to difficulties with speech, chewing, and biting. Its etiology is multifactorial, involving a combination of genetic, environmental, and developmental factors. Genetic studies have identified specific genes and signaling pathways involved in jaw growth, tooth eruption, and dental occlusion that may contribute to open bite development. Understanding the genetic and epigenetic factors contributing to skeletal open bite is crucial for developing effective prevention and treatment strategies. A thorough manual search was undertaken along with searches on PubMed, Scopus, Science Direct, and Web of Science for relevant studies published before June 2022. RCTs (clinical trials) and subsequent observational studies comprised the included studies. Orthodontic treatment is the primary approach for managing open bites, often involving braces, clear aligners, or other orthodontic appliances. In addition to orthodontic interventions, adjuvant therapies such as speech therapy and/or physiotherapy may be necessary. In some cases, surgical interventions may be necessary to correct underlying skeletal issues. Advancements in technology, such as 3D printing and computer-assisted design and manufacturing, have improved treatment precision and efficiency. Genetic research using animal models, such as the Collaborative Cross mouse population, offers insights into the genetic components of open bite and potential therapeutic targets. Identifying the underlying genetic factors and understanding their mechanisms can lead to the development of more precise treatments and preventive strategies for open bite. Here, we propose to perform human research using mouse models to generate debatable results. We anticipate that a genome-wide association study (GWAS) search for significant genes and their modifiers, an epigenetics-wide association study (EWAS), RNA-seq analysis, the integration of GWAS and expression-quantitative trait loci (eQTL), and micro-, small-, and long noncoding RNA analysis in tissues associated with open bite in humans and mice will uncover novel genes and genetic factors influencing this phenotype

The proteasome controls ESCRT-III–mediated cell division in an archaeon

INTRODUCTION: Eukaryotes likely arose from a symbiotic partnership between an archaeal host and an alpha-proteobacterium, giving rise to the cell body and the mitochondria, respectively. Because of this, a number of proteins controlling key events in the eukaryotic cell division cycle have their origins in archaea. These include ESCRT-III proteins, which catalyze the final step of cytokinesis in many eukaryotes and in the archaeon Sulfolobus acidocaldarius. However, to date, no archaeon has been found that harbors homologs of cell cycle regulators, like cyclin-dependent kinases and cyclins, which order events in the cell cycle across all eukaryotes. Thus, it remains uncertain how key events in the archaeal cell cycle, including division, are regulated. RATIONALE: An exception to this is the 20S proteasome, which is conserved between archaea and eukaryotes and which regulates the eukaryotic cell cycle through the degradation of cyclins. To explore the function of the 20S proteasome in the archaeon S. acidocaldarius, we determined its structure by crystallography and carried out in vitro biochemical analyses of its activity with and without inhibition. The impact of proteasome inhibition on cell division and cell cycle progression was examined in vivo by flow cytometry and super-resolution microscopy. Following up with mass spectrometry, we identified proteins degraded by the proteasome during division. Finally, we used molecular dynamics simulations to model the mechanics of this process. RESULTS: Here, we present a structure of the 20S proteasome of S. acidocaldarius to a resolution of 3.7 Å, which we used to model its sensitivity to the eukaryotic inhibitor bortezomib. When this inhibitor was added to synchronous cultures, it was found to arrest cells mid-division, with a stable ESCRT-III division ring positioned at the cell center between the two separated and prereplicative nucleoids. Proteomics was then used to identify a single archaeal ESCRT-III homolog, CdvB, as a key target of the proteasome that must be degraded to enable division to proceed. Examining the localization patterns of CdvB and two other archaeal ESCRT-III homologs, CdvB1 and CdvB2, by flow cytometry and super-resolution microscopy revealed the sequence of events that leads to division. First, a CdvB ring is assembled. This CdvB ring then templates the assembly of the contractile ESCRT-III homologs, CdvB1 and CdvB2, to form a composite division ring. Cell division is then triggered by proteasome-mediated degradation of CdvB, which allows the CdvB1:CdvB2 copolymer to constrict, pulling the membrane with it. During constriction, the CdvB1:CdvB2 copolymer is disassembled, thus vacating the membrane neck to drive abscission, yielding two daughter cells with diffuse CdvB1 and CdvB2. CONCLUSION: This study reveals a role for the proteasome in driving structural changes in a composite ESCRT-III copolymer, enabling the stepwise assembly, disassembly, and contraction of an ESCRT-III–based division ring. Although it is not yet clear how proteasomal inhibition prevents S. acidocaldarius cells from resetting the cell cycle to initiate the next S phase, these data strengthen the case for the eukaryotic cell cycle regulation having its origins in archaea

Mastering Electro-Mechanical Dynamics of Large Off-Shore Direct-Drive Wind Turbine Generators

The ever growing population of human beings on earth introduces the challenge of providing affordable, sustainable energy for everyone. Emerging markets, such as China, India or Brazil, quench their thirst for cheap energy by fossil fuels and nuclear power. At the same time researchers from all over the globe warn the public of the advent of a new, civilisation threatening disaster: climate change. Over the last two centuries mankind has gotten used to cheap but polluting energy provided by burning coal, gas and oil. The challenge arises in the form of the transition of our current economy towards a sustainable way of living. Renewable energy sources such as wind, tidal currents, the sun and geothermal heat have seen enourmous growth rates since the early nineties, as they are seen as the best approach to overcome this challenge. Of these renewable energy sources, wind energy is one that has received major attention. In the quest for expanding wind energy capacity, focus has shifted towards the sea in recent years. The potential energy yield is higher off-shore caused by higher average wind speeds. Maintenance and availability are key issues off-shore, due to the more complex logistics. In recent years, the price of on-shore wind energy has decreased to a level that is competitive with prices for energy from some types of fossil fuel. However, the prices for off-shore wind energy remain above the ones of fossil fuels. It is, thus, not surprising that the reduction of off-shore wind energy costs is one of the main innovation drivers within the wind industry. With the advent of off-shore wind energy more and more companies started investigating a new turbine topology called direct-drive wind turbines. This turbine type eliminates the gearbox found in other types of wind turbines, as this might lead to increased availability and lower maintenance costs. In the search for the best design of direct-drive wind turbines, every part of the turbine is investigated, analysed, measured and optimised to improve the functionality of that part. At the heart of the turbine, where the mechanical is transformed into electrical energy, is the generator. Also this component needs to be optimised with respect to weight and efficiency. This thesis aims to find the structural design that optimally utilises the mass of the generator structure to minimise deformation. This is done for the dynamic loads encountered in the generator. Special focus is given to the interaction between the structural dynamics and the magnetic field. This is important as the interaction between these two physical domains can lead to unexpected dynamic behaviour of the system. In Part I of this thesis, the modelling techniques that accurately include the interaction between the structural part of the turbine and the magnetic field in the generator are introduced. These techniques can, for the first time, predict the modal parameter changes, including damping changes, due to the interaction by forming a monolithic eigenvalue problem of the coupled system. The model neglects certain nonlinear influences on the dynamics, such as hysteresis and saturation. Its ability to predict changes of the modal parameters is validated by vibration measurements of a magneto-mechanical coupled system. Furthermore, this part develops new methods to handle huge magneto-mechanical coupled models that emerge when magnetic fields and structural dynamics of a direct-drive wind turbine are modelled. The bottleneck is the memory requirements of the monolithic formulation that makes it necessary to solve for all degrees of freedom simultaneously. Part II applies the techniques developed in Part I to the generator of the XD-115, a 5 MW direct-drive wind turbine and conducts the first two-way coupled analysis of such a generator type. The detailed dynamic analysis of the generator gives new insights in the dynamic behaviour of the generator. Furthermore, the eigenfrequencies, modes and possible causes for excitation are identified. An experimental validation of the XD-115 models was conducted using in-situ experimental and operation modal analyses. Various techniques are compared for the challenging task of exciting the rotor structure. In the second part of Part II, the loads identified during the dynamic analysis are used as load case for a structural optimisation. Topology and shape optimisation were used to identify the optimal mass distribution for the rotor structure that minimises the deformation in the air gap. This way, the weight of the structure could be reduced significantly without compromising the static and dynamic performance of the generator structure. During the optimisation the suitability and potential of topology optimisation for direct-drive wind turbines was evaluated. Although the introduced methodology can be applied to any electric machine, the implications for direct-drive wind turbine generators are most significant, as for these machines the ratio between produced torque and weight is especially high. Important influences on and encountered challenges for improving the design are collected to improve future turbine designs.PMEMechanical, Maritime and Materials Engineerin

The ICF comprehensively covers the spectrum of health problems encountered by health professionals in patients with musculoskeletal conditions

Objectives: The objective of this study was to investigate, whether the International Classification of Functioning, Disablity and Health (ICF) comprehensively covers the spectrum of health problems encountered by medical doctors and physiotherapists in patients with musculoskeletal conditions. Methods: A worldwide e-mail survey with questionnaires that requested lists of relevant areas in the ICF components—body functions, body structures, activities and participation, and environmental factors—in patients with rheumatoid arthritis, osteoarthritis, low back pain and osteoporosis was conducted. The suitability of linking the named concepts to the ICF as well as the precision of the linking was characterized by assigning the concepts to six groups. Results: All concepts that were named by the experts could be linked to the ICF, with the exception of personal factors. Between 32% (environmental factors) and 51% (activities and participation) of the named concepts were linked to an ICF category with an identical meaning and the same grade of precision. All other named concepts were linked to ICF categories with a lower level of precision, or encompassed more than one ICF category, or were linked to an ICF category with a related, but not identical meaning. Conclusions: The ICF covers comprehensively the spectrum of problems encountered in patients with musculoskeletal conditions by clinical experts throughout the world. This strengthens the validity of the ICF in the view of the users and will encourage the use of ICF-based applications such as the ICF checklist and the now-developed ICF Core Sets

Rehabilitationsmanagement in der praxis unter anwendung der internationalen klassifikation der funktionsfähigkeit, behinderung und gesundheit (ICF)

Purpose: Rehabilitation aims to enable people experiencing or likely to experience disability to achieve and maintain optimal functioning. Consequently, the assessment of functioning is the starting point of a patient and goal oriented rehabilitation process. Within the International Classification of Functioning, Disability and Health (ICF) rehabilitation practitioners can rely for the first on a worldwide accepted model providing a universal language for the description and classification of functioning. To take advantage of the ICF in rehabilitation management there is a need to develop appropriate ICF Tools for clinical practice. Such ICF Tools, integrating the model and the classification of the ICF, have to be integrated in a problem solving approach provided by the Rehab-Cycle.Results: ICF Tools have been developed for the use in the different steps of the Rehab-Cycle. Existing ICF Core Sets in combination with the use of ICF Qualifiers were the basis for this development. In clinical practice, these ICF Tools allow the description of a functioning state, the illustration of the patient's experience of functioning and the relation between rehabilitation goals and appropriate intervention targets, an overview over required resources to improve specific aspects of human functioning and finally, the changes in functioning states following rehabilitative interventions. The ICF Tools support a common understanding of functioning and the communication among team members when used in multidisciplinary rehabilitation.Discussion and Conclusions: The development of electronic documentation systems, the assignment of standardized instruments to ICF categories and the operationalization of the ICF Qualifiers can contribute to further improvements of ICF based rehabilitation management in the future