ß-lactam enzyme antibiotic is one of the most effective chemotherapy medicine in treating bacteria infection. Inhibitor of metal 2-lactam enzyme is an important topic in clinical medical science during the historic development of antibiotics in the past sixty years since the discovery of penicillin. The most common resistance mechanism is to hydrolysis the enzyme of these antibiotics, known as ß-lactam enzyme. Metal ß-lactam enzyme has a very rare wide substrate surface, which can prohibit the movement of bicyclic ß-lactam antibiotics. The research focus in medical science is concentrated on ß-lactam enzyme’s structure and inhibitor design.

In my own work, an important protein system, named as metal ß-lactam enzyme of arc-shaped stem fungus, is investigated theoretically. The three-dimensional structure of metal ß-lactam enzyme of arc-shaped stem fungus is obtained by means of homology modeling and molecular dynamics simulation. Additionally, active sites have been predicted according to the catalysis mechanism of metal ß-lactam enzyme of arc-shaped stem fungus. Finally, our computed results are compared with previous reports of relevance. The differences have been analyzed and discussed.

The spray freeze-drying system is a type of freeze-drying method. This technology is a hybrid pharmaceutical manufacturing technology that combines the spray drying and freeze-drying which are existing manufacturing technologies [1].

Its introduction into the pharmaceutical industry has begun to be considered as an alternative manufacturing method to conventional freeze-drying technology [2].

Spray freeze-drying system can be applied to various pharmaceuticals regardless of modality. This technology has the potential to be a useful solution to formulation issues that were difficult to solve with conventional freeze-drying technology. Thus, it is expected that this technology, which can be used from the perspective of both formulation design and commercial manufacturing, will become more widespread in the future.

In this presentation, the case studies in Shionogi using sucrose and model liposomes with a view to applying spray freeze-drying to pharmaceutical development will be addressed [3]. The former case is a study aimed at applying spray freeze-drying to low molecular weight compounds, and the latter case is a study aimed at applying spray freeze-drying to soft materials.

Education is not only one of the 17 United Nations Sustainable Development Goals (SDG) [1] but it also plays a detrimental role in achieving sustainability [240]. Education implies active and passive access to knowledge, which comprises unbiased access to scientific literature as a major component. Up to the 1980s this meant textbooks and journal articles, that had to be bought by the recipient or borrowed from a local or remote library free of charge or for a comparably small fee.

An additional source of information came in the 1990s when the internet entered offices, and private households. Initially, all the information was publically available free of charge, but eventually commercialization set in.

On the other end of the spectrum are the scientists, whose research culminates in the generation of knowledge, evident by publication. Simplified, a researcher builds his/her scientific reputation on the number of publications authored. Publications became -and still are- a kind of virtual currency in academia – “Publish or perish”.

Comparing the supply chain of knowledge with that of typical other goods, there always used to be a slight mismatch between the flow of goods and services and the flow of money. There is a strong similarity between common goods and books, where supplier and author are compensated (e.g. 10% of sales price for authors) and a quality check is incorporated; either at supplier, wholeseller or retail shop, and this quality assurance (QA) function might be internal or outsourced. However, usually scientific print journals did not pay the authors for content nor were peer reviewers paid. The customer or reader is charged for the goods or literature received. However, libraries served as a cost effective way to make knowledge cost effectively available.

The situation intiensified and the mismatch became even more evident since the introduction of open access or public access schemes: To allow open access for the user, the publisher requires the inversion of monetary flow through reimbursment by the author. This means the content provider now also provides the financial funding (typically a mid four-figure USD amount per publication)!

Especially early career scientists are hurt the most by open access publishing schemes: On the one hand they need to build their reputation by publishing their findings, but it is not only the publication itself that counts; it is also the number of citations that one receives. The lower the threshold for readers the more citaions. Any kind of restricted access poses a hurdle for the readers and the likelihood for being cited diminishes.

On the other hand, without reputation it is hard to get funding for research work and if the scarce funds have to go to the publisher, then there’s hardly any leftover for research (Publish and perish)  and vice versa. A vicious circle right from the start that is hard to overcome; especially if the job of the scientist also comprises teaching (fulfilling educational service aka spreading knowledge to the students) by lecturing, supervising and conducting lab courses).

This article describes approaches to escape this conundrum. 

We first review the initiation by two of us (R. M. S. and T. V.) [1] of the mathematical representation of life, intended as the difference between organic and inorganic molecules, via the Lie-admissible hyperstructural branch of hadronic mechanics representing the size of biological molecules, their contact thus non-Hamiltonian interactions and the irreversibility over time. We then review and expand the studies done in the subsequent paper [2] showing that: 1) The time irreversible hadronic representation of life can be obtained via the addition of the symmetric Jordan brackets to reversible quantum mechanical Lie brackets; 2) The Lie and Jordan admissible axiomatic formulation of hadronic medicine with non-linear, non-local an non Hamiltonian entanglements of molecular constituents operating without the use of a known form of energy; 3) The smooth connection between hadronic uncertainties at small distances and full Einsteinian determinism at classical distances; 4) The quantitative representation by hadronic medicine of some actions by biological entities beyond our sensory perception; 5) The expected diagnostic and curative values of hadronic medicine.

During storage, transport, dilution and intravenous (i.v.) administration, mAbs are exposed to different stressors, including artificial and indoor ambient light, which can compromise their efficacy and safety. Light can induce concentration-dependent aggregation, leading to a measurable reduction in the drug's ability to bind its target The surface tensiometry properties of monoclonal antibodies (mAbs) were recently characterized using the Solid-like Methodology (SLM) [1] applying the Contact Angle Method (CA) [2]. The SLM consists in the deposition of a hydrophobic, lipophobic and self-repellent “liquid film”, called polyperfluorometylisopropyl ether (PFPE) [3] used as “solid substrate” for the characterization of liquid systems droplets [4]. This SLM consents the determination of Surface Tension (ST; mN/m), Dispersion Component (DC; mN/m) and Polar Component (PC; mN/m) of liquids without the influence of friction forces and surface roughness and was largely applied in the field of pharmaceutical technology [5]. The Well methodology (WM) [5] derives from the concept of Solid-like Methodology (SLM); unlike the SLM, the WM consists in the deposition of an amount of PFPE (PFPEw) leaved in a ceramic concave support (well). When a drop of liquid comes in contact with the surface of the PFPEw, a characteristic meniscus is formed caused by the hydrophilic/lipophilic ratio of the liquid (corresponds to its surface chemistry) in relation to the hydrophobic, lipophobic and self-repellent properties of PFPEw at the interface. The WM was here used to determine the surface tensiometry properties of human blood (Hb, G.M. droplets) and its variations after the addition with Nivolumab/Opdivo® (Opdivo samples/Hb complex system) as such and diluted in glucose and NaCl before and after light treatment with 720.0 and 10.460 KJ/m². The surface tensiometry parameter used here is the Vertical Drop Speed (VDS: dSA/dt) which measures the rate at which a drop of mAb sample spreads vertically at the interface with PFPEw. As first result, the VDS Opdivoâ formulation values (6.3E-05±4.8E-05) tend to decrease strongly after treatment with 720.0 KJ/m² (2.9E-05±7.9E-06) and more at 10460 KJ/m² (2.2E-05±8E-06) due to the degradation of Opdivoâ under the light stressor. Differently, the Hb/Opdivoâ complex system VDS values (9.7E-05±5.3E-05) are quite the same after 720.0 KJ/m² (1.0E-04±4.0E-05) and slightly decrease only after 10460 KJ/m² (7.3E-05±3.6E-05). This result appears to be correlated with the presence of blood components in the system, which maintains  high VDS values due to the strong affinity between mAb and blood components. The presence of 5% glucose (Opdivoâ-glu) as cosolvent reveals the equilibrium between Opdivoâ-glu (3.4E-05±9.1E-06) and blood (9.6E-05±4.6E-05) in the Hb/Opdivoâ-glu complex system (7.5E-05±3.1E-05). The treatment of Opdivoâ-glu with 720.0 KJ/m² and 10460 KJ/m² causes, respectively, slight (Opdivoâ-glu; 2.8E-05±5.2E-06, Hb/Opdivoâ-glu; 8.7E-05±3.8E-05, blood; 9.6E-05±4.6E-05) and strong (Opdivoâ-glu; 5.5E-05±1.6E-05, Hb/Opdivoâ-glu; 1.7E-04±8.1E-05, blood; 9.6E-05±4.6E-05) equilibrium decreases due to the great increase of VDS of Hb/Opdivoâ-glu (10460 KJ/m²). This seems due to the increase of aggregates in Opdivoâ-glu after light treatments amplified by the presence of blood components. The presence of 0.9% NaCl demonstrates a disequilibrium between Opdivoâ-NaCl (6.2E-05±2.1E-05) and blood (9.6E-05±4.6E-05) due to lower VDS value of Hb/Opdivoâ-NaCl.(1.4E-05±1.0E-06). That equilibrium is reached after treatment of Opdivoâ-NaCl with 720.0 KJ/m² (Opdivoâ-NaCl; 4.8E-05±1.4E-05, Hb/Opdivoâ-glu; 7.1E-05±2.7E-05, blood; 9.6E-05±4.6E-05) and marked decreased after treatment with 10460 KJ/m² (Opdivoâ-NaCl; 4.7E-05±1.2E-05, Hb/Opdivoâ-glu; 1.2E-04±5E-05, blood; 9.6E-05±4.6E-05). However, the increase of Hb/Hb/Opdivoâ-glu as aggregates in NaCl irradiated Opdivo are formed in less amount. With this work we demonstrate the different behaviour of dark and irradiated samples and the difference between undiluted and diluted (NaCl and glucose) Opdivo samples when come in contact with blood. Therefore, we try to mimic the i.v. administration of this drug: when aggregation takes place, mostly under the light exposure and even more in glucose solution, the WM can promptly detect the physical differences among the samples. Our findings indicate that mAbs should be protected from light, especially during prolonged i.v. administration periods, to avoid aggregate formation and potentially reduction of their therapeutic activity.

Protein-Protein Interactions (PPI) mediate numerous processes in cells in health and disease. However, it is extremely challenging to make them drug targets. This is especially true for intrinsically disordered proteins (IDPs). The research in our lab focuses on using peptides for the quantitative biophysical and structural analysis of PPI. Based on this, we develop lead peptides that modulate PPI for therapeutic purposes. Our latest research directions include:

1. Control of condensation and aggregation of proteins by multiphosphorylation: Specific phosphorylation patterns dictate the activity and interactions of many proteins. We developed new methods for rapid and efficient of peptide libraries with distinct multi-phosphorylation patterns. This enables systematic studying at the level of isolated protein domains. We used these tools to elucidate how multi-phosphorylation regulates the self-assembly and activity of two IDPs: the cancer-related APC protein and the neurodegenerative diseases-related Tau protein.
2. Inhibiting structured and disordered domains simultaneously: We developed a strategy for inhibiting the structured and disordered hot spots of an interaction using chimeric peptides that contain both structured and disordered parts, which target both structured and disordered hot spots at the same protein.  The approach is demonstrated for inhibiting the anti-apoptotic iASPP protein.  
3. Specific targeting of cancer cells by a designed peptide: We developed a peptide that specifically targets cancer cells and kills them by activating cell death pathways. The peptide is derived from the NAF-1 protein and acts by selectively penetrating the plasma membrane of cancer cells and targeting their mitochondria-ER network. 
4. Inhibiting protein aggregation in disease: Strategies to inhibit aggregation in disease usually focus on highly specific inhibitors for one hotspot but have not made a clinical impact yet. We developed a systematic approach for designing chaperone-like peptides targeting early aggregation stages populated by dynamic precursors, before a mechanistic differentiation takes place. Peptides designed using this strategy inhibited aggregation of disease-related proteins that aggregate in completely different pathways and may serve as general lead compounds against numerous protein aggregation diseases.

CFD (computational fluid dynamics) modelling has gained a lot of momentum throughout the last decade and also becomes a valuable tool in biopharma. Taking the example of mixing in Single Use System (SUS) Mixers as an example, this paper discusses the huge advantages that CFD modelling brings for gaining deeper insights into mixing in these novel mixers but also shows the downsides of CFD modelling in general and its environmental impact under sustainability aspects and how Super-Designed Modelling can help significantly.

Mixing liquids is a basic operation frequently performed in the biopharmaceutical sector for both small-scale (beakers or flasks) and large-scale, e.g. bioreactors. In bioreactors, upstream as well as downstream processes are key when compounding, pooling, mixing and filling from large tanks.

So far, smooth-walled stainless-steel containers with standardized lapper bottoms have mostly/ widely been used on a larger scale together with common mixing impellers (located usually around the lower third of the container) For these set-ups mixing processes are well established, characterized extensively and generally scaled using P/V (energy input as a power to volume ratio).

For various business and regulatory reasons, efforts have recently been made to switch to Single Use Systems (SUS) for mixing as well/additionally. Here, specially sized three-dimensional plastic bags are hooked into a support cover. To minimize shear stress on biopharmaceuticals, the SUS impellers have entirely different shapes compared to those that were previously common; they sit floating in cup-shaped recesses at the bottom of the bag and are usually also eccentrically displaced. In addition, even when carefully inserted into the support cover and being filled, the bags do not form a smooth wall but have a creased or wrinkled surface.

When submitting new drugs for approval, the authorities require comprehensive knowledge of the product not only regarding the pharmacological, toxicological and clinical aspects, but also regarding the formulation and manufacturing process, which includes mixing.

Accordingly, the characterization of mixing processes in SUS is of great importance.

While experimental mixer validation is usually unproblematic in small-scale, large-scale experimental mixing tests involving extreme parameters (e.g. different speeds, filling volumes, etc.) present almost insurmountable obstacles, because the products are not only extremely expensive in larger quantities but also are usually not available to a sufficient extent in the early phases of development.

Typically, modelling approaches come into play at such a stage [1].

Computational fluid dynamics (CFD) simulations offer a path forward to gain insights into mixing behavior despite these challenges.

However, CFD simulations require a lot of computational power, especially for high-resolution simulations. Several days of computing are rule rather than exception, even on high performance multi core GPU clusters. The energy consumption of a simple 50L mixing, resembling only minutes of real time operation, might require approx. 43kWh. This equals the power consumption of a fridge/freezer combination operated for 3 months or 2 months of operating a laptop 24/7 under normal load.

Superdesigned modelling (SDM) is an approach to tackle the two downsides of CFD modelling at once: Time and energy consumption. The general questions to be answered by CFD simulation of mixing are usually:

1. What is the required mixer speed for sufficient mixing, while minimizing splashing, foaming, and air incorporation?
2. What is the required mixing time thereof?
3. What is the extent of shear stress on a biologic drug substance?

This means that from the vast amount of three-dimensional data, which are generated over tiny high resolution timesteps, only three(!) computed numbers make up/comprise the relevant output. As inputs there are mainly fill level, proportion of liquids to be mixed, their densities and viscosities.

Developing Design of Experiments (DOEs) around simulations by using these inputs as factors for a DOE and conducting the appropriate simulations forms the foundation for SDM.

Although the number of required simulations for a given mixer/impeller combination is kept to a minimum, the performed and analyzed DOE allows for an interpolation of data for any given input combination. As a result, the model can predict output parameters without running additional CFD simulations. Since the model also serves as an analytical equivalence of the simulations, it could be used to derive underlying functional dependencies and uncover even more knowledge around mixing.

Young researchers in academia face a lot of hurdles while establishing their scientific careers. They are caught up in a series of traps where one can’t be overcome by overcoming all the others as well: time, funding, publishing, research, teaching, being present at conferences, expanding their skillset, building and getting into networks etc. All those topics are intertwined; all shall be served at once and all at the fullest extent possible.

Consequentially, this situation has a high potential of becoming a vicious circle unless it is broken at one or more points.

Here, foundations can set in and help in multiple ways to break the circle and overcome this conundrum effectively. One example is the Galenus-Privatstiftung [1], a non-profit scientific foundation that aims to support postdocs, habilitation candidates, assistant and junior professors in the field of pharmaceutical technology and biopharmacy. The foundation awards the Galenus Supports, the Technology Prize, enables visiting professorships as well as international workshops.

Radioactive waste of fission reactors is a problem and needs special treatment for keeping it at a safe location, so that radioactive waste can decay without contaminating the environment. Radioactive waste is the product of the nuclear absorption of neutrons (n, g) in a fission nuclear power plant for achieving electricity without using fossil fuels releasing CO₂. ¹Interestingly, this nuclear reaction (n, g) can be reversed by inducing a photonuclear reaction (g, n) If the corresponding g - ray source is available. Interestingly, this g - ray source has to be in resonance with the original (n, g) reaction. Angelo Comunetti could show with his experiments that he could reverse the reaction (n, g) of ¹⁹⁷Au->¹⁹⁸Auand in addition induce (g, n) reactions of ¹⁹⁷Au -> ¹⁹⁶Pt. Thus, Angelo Comunetti started to doubt that Neutron Activation Analysis NAA is always working since his subsequent NAA showed that no more Au was present…

Interestingly, Angelo Comunetti also was able to demonstrate that he could induce the photonuclear reaction (g, n) in case of ²⁴Na -> leading to ²³Na and to (g, n) of ²³Na leading to ²²Na, respectively to the volatile ²²Ne.

Conclusion: The original reaction (g, n) is reversible and it is feasible to transform the radioactive waste of fission power plants into non-radioactive waste, which does not need to be buried in a safe location.