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Microarray-based experiments revealed that thyroid hormone triiodothyronine (T3) enhanced the binding of Cy5-labeled ATP on heat shock protein 90 (Hsp90). By molecular docking experiments with T3 on Hsp90, we identified a T3 binding site (TBS) near the ATP binding site on Hsp90. A synthetic peptide encoding HHHHHHRIKEIVKKHSQFIGYPITLFVEKE derived from the TBS on Hsp90 showed, in MST experiments, the binding of T3 at an EC50 of 50 μM. The binding motif can influence the activity of Hsp90 by hindering ATP accessibility or the release of ADP.
Thermo-chemical conversion of cucumber peel waste for biobased energy and chemical production
(2022)
Therapeutic Treatments for Osteoporosis-Which Combination of Pills Is the Best among the Bad?
(2022)
Osteoporosis is a chronical, systemic skeletal disorder characterized by an increase in bone resorption, which leads to reduced bone density. The reduction in bone mineral density and therefore low bone mass results in an increased risk of fractures. Osteoporosis is caused by an imbalance in the normally strictly regulated bone homeostasis. This imbalance is caused by overactive bone-resorbing osteoclasts, while bone-synthesizing osteoblasts do not compensate for this. In this review, the mechanism is presented, underlined by in vitro and animal models to investigate this imbalance as well as the current status of clinical trials. Furthermore, new therapeutic strategies for osteoporosis are presented, such as anabolic treatments and catabolic treatments and treatments using biomaterials and biomolecules. Another focus is on new combination therapies with multiple drugs which are currently considered more beneficial for the treatment of osteoporosis than monotherapies. Taken together, this review starts with an overview and ends with the newest approaches for osteoporosis therapies and a future perspective not presented so far.
The Chemotype of Chromanones as a Privileged Scaffold for Multineurotarget Anti-Alzheimer Agents
(2022)
The utilization of simulation procedures is gaining increasing attention in the product development of extrusion blow molded parts. However, some simulation steps, like the simulation of shrinkage and warpage, are still associated with uncertainties. The reason for this is on the one hand a lack of standardized interfaces for the transfer of simulation data between different simulation tools, and on the other hand the complex time-, temperature- and process-dependent material behavior of the used semi crystalline polymers. Using a new vendor neutral interface standard for the data transfer, the shrinkage analysis of a simple blow molded part is investigated and compared to experimental data. A linear viscoelastic material model in combination with an orthotropic process- and temperature-dependent thermal expansion coefficient is used for the shrinkage prediction. A good agreement is observed. Finally, critical parameters in the simulation models that strongly influence the shrinkage analysis are identified by a sensitivity study.
A precise characterization of substances is essential for the safe handling of explosives. One parameter regularly characterized is the impact sensitivity. This is typically determined using a drop hammer. However, the results can vary depending on the test method and even the operator, and it is not possible to distinguish the type of decomposition such as detonation and deflagration. This study monitors the reaction progress by constructing a drop hammer to measure the decomposition reaction of four different primary explosives (tetrazene, silver azide, lead azide, lead styphnate) in order to determine the reproducibility of this method. Additionally, further possible evaluation methods are explored to improve on the current binary statistical analysis. To determine whether classification was possible based on extracted features, the responses of equipped sensor arrays, which measure and monitor the reactions, were studied and evaluated. Features were extracted from this data and were evaluated using multivariate methods such as principal component analysis (PCA) and linear discriminant analysis (LDA). The results indicate that although the measurements show substance specific trends, they also show a large scatter for each substance. By reducing the dimensions of the extracted features, different sample clusters can be represented and the calculated loadings allow significant parameters to be determined for classification. The results also suggest that differentiation of different reaction mechanisms is feasible. Testing of the regressor function shows reliable results considering the comparatively small amount of data.
Characterization methods of pressure sensitive adhesives (PSA) originate from technical bonding and do not cover relevant data for the development and quality assurance of medical applications, where PSA with flexible backing layers are adopted to human skin. In this study, a new method called RheoTack is developed to determine (mechanically and optically) an adhesion and detaching behavior of flexible and transparent PSA based patches. Transdermal therapeutic systems (TTS) consisting of silicone-based PSAs on a flexible and transparent backing layer were tested on a rotational rheometer with an 8 mm plate as a probe rod at retraction speeds of 0.01, 0.1, and 1 mm/s with respect to their adhesion and detaching behavior in terms of force-retraction displacement curves. The curves consist of a compression phase to affirm wetting; a tensile deformation phase intercepting stretching, cavity, and fibril formation; and a failure phase with detaching. Their analysis provides values for stiffness, force, and displacement of the beginning of fibril formation, force and displacement of the beginning of a failure due to fibril breakage and detaching, as well as corresponding activation energies. All these parameters exhibit the pronounced dependency on the retraction speed. The force-retraction displacement curves together with the simultaneous video recordings of the TTS deformation from three different angles (three cameras) provide deeper insight into the deformation processes and allow for interpreting the properties’ characteristics for PSA applications.
SLC6A14 (ATB0,+) is unique among SLC proteins in its ability to transport 18 of the 20 proteinogenic (dipolar and cationic) amino acids and naturally occurring and synthetic analogues (including anti-viral prodrugs and nitric oxide synthase (NOS) inhibitors). SLC6A14 mediates amino acid uptake in multiple cell types where increased expression is associated with pathophysiological conditions including some cancers. Here, we investigated how a key position within the core LeuT-fold structure of SLC6A14 influences substrate specificity. Homology modelling and sequence analysis identified the transmembrane domain 3 residue V128 as equivalent to a position known to influence substrate specificity in distantly related SLC36 and SLC38 amino acid transporters. SLC6A14, with and without V128 mutations, was heterologously expressed and function determined by radiotracer solute uptake and electrophysiological measurement of transporter-associated current. Substituting the amino acid residue occupying the SLC6A14 128 position modified the binding pocket environment and selectively disrupted transport of cationic (but not dipolar) amino acids and related NOS inhibitors. By understanding the molecular basis of amino acid transporter substrate specificity we can improve knowledge of how this multi-functional transporter can be targeted and how the LeuT-fold facilitates such diversity in function among the SLC6 family and other SLC amino acid transporters.
The epithelial sodium channel (ENaC) is a heterotrimeric ion channel that plays a key role in sodium and water homeostasis in tetrapod vertebrates. In the aldosterone-sensitive distal nephron, hormonally controlled ENaC expression matches dietary sodium intake to its excretion. Furthermore, ENaC mediates sodium absorption across the epithelia of the colon, sweat ducts, reproductive tract, and lung. ENaC is a constitutively active ion channel and its expression, membrane abundance, and open probability (PO) are controlled by multiple intracellular and extracellular mediators and mechanisms [9]. Aberrant ENaC regulation is associated with severe human diseases, including hypertension, cystic fibrosis, pulmonary edema, pseudohypoaldosteronism type 1, and nephrotic syndrome [9].
Silicon carbide and graphene possess extraordinary chemical and physical properties. Here, these different systems are linked and the changes in structural and dynamic properties are investigated. For the simulations performed a classical molecular dynamic (MD) approach was used. In this approach, a graphene layer (N = 240 atoms) was grafted at different distances on top of a 6H-SiC structure (N = 2400 atoms) and onto a 3C-SiC structure (N = 1728 atoms). The distances between the graphene and the 6H are 1.0, 1.3 and 1.5 Å and the distances between the graphene layer and the 3C-SiC are 2.0, 2.3, and 2.5 Å. Each system has been equilibrated at room temperature until no further relaxation was observed. The 6H-SiC structure in combination with graphene proves to be more stable compared to the combination with 3C-SiC. This can be seen well in the determined energies. Pair distribution functions were influenced slightly by the graphene layer due to steric and energetic changes. This becomes clear from the small shifts of the C-C distances. Interactions as well as bonds between graphene and SiC lead to the fact that small shoulders of the high-frequency SiC-peaks are visible in the spectra and at the same time the high-frequency peaks of graphene are completely absent.
Process-induced changes in the morphology of biodegradable polybutylene adipate terephthalate (PBAT) and polylactic acid (PLA) blends modified with various multifunctional chainextending cross-linkers (CECLs) are presented. The morphology of unmodified and modified films produced with blown film extrusion is examined in an extrusion direction (ED) and a transverse direction (TD). While FTIR analysis showed only small peak shifts indicating that the CECLs modify the molecular weight of the PBAT/PLA blend, SEM investigations of the fracture surfaces of blown extrusion films revealed their significant effect on the morphology formed during the processing. Due to the combined shear and elongation deformation during blown film extrusion, rather spherical PLA islands were partly transformed into long fibrils, which tended to decay to chains of elliptical islands if cooled slowly. The CECL introduction into the blend changed the thickness of the PLA fibrils, modified the interface adhesion, and altered the deformation behavior of the PBAT matrix from brittle to ductile. The results proved that CECLs react selectively with PBAT, PLA, and their interface. Furthermore, the reactions of CECLs with PBAT/PLA induced by the processing depended on the deformation directions (ED and TD), thus resulting in further non-uniformities of blown extrusion films.
Sensoren können verschiedene Aufgaben erfüllen, wie beispielsweise die Optimierung von Prozessen, die Interaktion zwischen Geräten oder die Verbesserung der zivilen Sicherheit. [1–3] Ihr Bedarf für die Industrie oder den Alltag wächst seit Jahren stetig. Besonders mobile Gassensoren sind von großem Interesse. Jedoch ist ihre Anwendung meist durch ihre integrierte Batterie begrenzt. Gassensoren ohne oder mit einem nur sehr geringen Energieverbrauch stehen daher im Interesse bei neuen Anwendungsgebieten, beispielsweise im Brandschutz oder in der Textilindustrie. [4,5] Die Sensoren könnten zum Beispiel in die Textilien einer persönlichen Schutzausrüstung eingearbeitet werden und durch einen Farbumschlag die Anwesenheit eines Gases oder die Überschreitung des Grenzwertes toxischer Substanzen anzeigen.
P30 - Das Elektrospinnen von halbleitenden Zinndioxidfasern für die Detektion von Wasserstoff
(2022)
Das Ziel dieser Arbeit ist die Entwicklung von dünnen keramischen Fasern als halbleitendes Sensormaterial zum Nachweis von Wasserstoff, möglichst bei Zimmertemperatur. Die elektrische Leitfähigkeit halbleitender Metalloxide ändert sich durch die Einwirkung von oxidierenden und reduzierenden Gasen auf die Oberfläche des Metalloxids. Dieser Effekt kann zur Messung der Gaskonzentration genutzt werden. Die Reaktion von Zinn(IV)-oxid mit Wasserstoff basiert auf der Reduktion des Zinn(IV)-oxids zum Zinn, wobei die Elektronen des Zinn(IV)-oxids im metallischen Zinn verbleiben und dort im nicht gebundenen Zustand zu einer Leitfähigkeitserhöhung beitragen. Die Reaktion des Wasserstoffes kann sowohl mit den Sauerstoffatomen des Oxids als auch mit adsorbierten Sauerstoffatomen an der Oxidoberfläche stattfinden.[ 6] Da die Reaktionen an der Oberfläche des Oxids stattfinden, sollten Sensoren mit einer großen Oberfläche im Vergleich zu metalloxidischen Bulkmaterialien eine höhere Empfindlichkeit aufweisen. [3] Die Verwendung von Fasern anstelle von Dünn- oder Dickschichten führt dabei zu einer besseren Sensitivität gegenüber Gasen.
Operating an ozone-evolving PEM electrolyser in tap water: A case study of water and ion transport
(2022)
While PEM water electrolysis could be a favourable technique for in situ sanitization with ozone, its application is mainly limited to the use of ultrapure water to achieve a sufficient long-time stability. As additional charge carriers influence the occurring transport phenomena, we investigated the impact of different feed water qualities on the performance of a PEM tap water electrolyser for ozone evolution. The permeation of water and the four most abundant cations (Na+, K+, Ca2+, Mg2+) is characterised during stand-by and powered operation at different charge densities to quantify underlying transport mechanisms. Water transport is shown to linearly increase with the applied current (95 ± 2 mmol A−1 h−1) and occurs decoupled from ion permeation. A limitation of ion permeation is given by the transfer of ions in water to the anode/PEM interface. The unstabilized operation of a PEM electrolyser in tap water leads to a pH gradient which promotes the formation of magnesium and calcium carbonates and hydroxides on the cathode surface. The introduction of a novel auxiliary cathode in the anolytic compartment has shown to suppress ion permeation by close to 20%.
Modern PCR-based analytical techniques have reached sensitivity levels that allow for obtaining complete forensic DNA profiles from even tiny traces containing genomic DNA amounts as small as 125 pg. Yet these techniques have reached their limits when it comes to the analysis of traces such as fingerprints or single cells. One suggestion to overcome these limits has been the usage of whole genome amplification (WGA) methods. These methods aim at increasing the copy number of genomic DNA and by this means generate more template DNA for subsequent analyses. Their application in forensic contexts has so far remained mostly an academic exercise, and results have not shown significant improvements and even have raised additional analytical problems. Until very recently, based on these disappointments, the forensic application of WGA seems to have largely been abandoned. In the meantime, however, novel improved methods are pointing towards a perspective for WGA in specific forensic applications. This review article tries to summarize current knowledge about WGA in forensics and suggests the forensic analysis of single-donor bioparticles and of single cells as promising applications.
Nanomedicine strategies were first adapted and successfully translated to clinical application for diseases, such as cancer and diabetes. These strategies would no doubt benefit unmet diseases needs as in the case of leishmaniasis. The latter causes skin sores in the cutaneous form and affects internal organs in the visceral form. Treatment of cutaneous leishmaniasis (CL) aims at accelerating wound healing, reducing scarring and cosmetic morbidity, preventing parasite transmission and relapse. Unfortunately, available treatments show only suboptimal effectiveness and none of them were designed specifically for this disease condition. Tissue regeneration using nano-based devices coupled with drug delivery are currently being used in clinic to address diabetic wounds. Thus, in this review, we analyse the current treatment options and attempt to critically analyse the use of nanomedicine-based strategies to address CL wounds in view of achieving scarless wound healing, targeting secondary bacterial infection and lowering drug toxicity.
Modeling of Creep Behavior of Particulate Composites with Focus on Interfacial Adhesion Effect
(2022)
Evaluation of creep compliance of particulate composites using empirical models always provides parameters depending on initial stress and material composition. The effort spent to connect model parameters with physical properties has not resulted in success yet. Further, during the creep, delamination between matrix and filler may occur depending on time and initial stress, reducing an interface adhesion and load transfer to filler particles. In this paper, the creep compliance curves of glass beads reinforced poly(butylene terephthalate) composites were fitted with Burgers and Findley models providing different sets of time-dependent model parameters for each initial stress. Despite the finding that the Findley model performs well in a primary creep, the Burgers model is more suitable if secondary creep comes into play; they allow only for a qualitative prediction of creep behavior because the interface adhesion and its time dependency is an implicit, hidden parameter. As Young’s modulus is a parameter of these models (and the majority of other creep models), it was selected to be introduced as a filler content-dependent parameter with the help of the cube in cube elementary volume approach of Paul. The analysis led to the time-dependent creep compliance that depends only on the time-dependent creep of the matrix and the normalized particle distance (or the filler volume content), and it allowed accounting for the adhesion effect. Comparison with the experimental data confirmed that the elementary volume-based creep compliance function can be used to predict the realistic creep behavior of particulate composites.
Mobiles Laser-Schneidsystem zur Unterstützung der USBV-Entschärfung und Beweissicherung (mobiLaS)
(2022)
Approximately 45% of global greenhouse gas emissions are caused by the construction and use of buildings. Thermal insulation of buildings in the current context of climate change is a well-known strategy to improve the energy efficiency of buildings. The development of renewable insulation material can overcome the drawbacks of widely used insulation systems based on polystyrene or mineral wool. This study analyzes the sustainability and thermal conductivity of new insulation materials made of Miscanthus x giganteus fibers, foaming agents, and alkali-activated fly ash binder. Life cycle assessments (LCA) are necessary to perform benchmarking of environmental impacts of new formulations of geopolymer-based insulation materials. The global warming potential (GWP) of the product is primarily determined by the main binder component sodium silicate. Sodium silicate's CO2 emissions depend on local production, transportation, and energy consumption. The results, which have been published during recent years, vary in a wide range from 0.3 kg to 3.3 kg CO2-eq. kg-1. The overall GWP of the insulation system based on Miscanthus fibers, with properties according to current thermal insulation regulations, reaches up to 95% savings of CO2 emissions compared to conventional systems. Carbon neutrality can be achieved through formulations containing raw materials with carbon dioxide emissions and renewable materials with negative GWP, thus balancing CO2 emissions.
Introduction of Matrix-Filler Adhesion to Modelling of Elastic Moduli of Particulate Composites
(2022)
Cube in cube elementary volume (EV) concept serves to predict a filler-content dependent Young´s moduli of particle filled composites using moduli of a matrix EM and a filler EF. Paul and Ishai-Cohen derived formulas for composites moduli considering different load transfer boundaries in the EV assuming a complete filler-matrix adhesion. In this paper it is confirmed that their models represent the upper and lower bounds, respectively, with the respect to the experimental data. However, in vast majority of composites a filler-matrix adhesion is not complete. Therefore, an adhesion factor kadh gaining values between 0 and 1 was introduced into Paul´s model to consider the reduced adhesion as the reduction of the filler-matrix contact area for glass beads filled in polar and unpolar thermoplastic matrices as well as elastomer. The evaluation of these composite systems provides reasonable adhesion coefficients of PA66 > PBT > PP > PE-LD >> BR. It was also found that stiffening only occurs if kadh exceeds the minimum value adhesion of root square of E(M) divided by E(F). The determined kadh correspond to scanning electron microscopy observations of the composites fracture surfaces. Additionally, finite element analysis of the cubic and hexagonal arrangements of the EV show that the stress distributions are different, but they affect the calculated moduli only for the filler volume contents exceeding 20 %. The introduction of the filler-matrix adhesion provides more reliable predictions of Young´s moduli of particulate composites.
Bonding wires made of aluminum are the most used materials for the transmission of electrical signals in power electronic devices. During operation, different cyclic mechanical and thermal stresses can lead to fatigue loads and a failure of the bonding wires. A prediction or prevention of the wire failure is not yet possible by design for all cases. The following work presents meaningful fatigue tests in small wire dimensions and investigates the influence of the R-ratio on the lifetime of two different aluminum wires with a diameter of 300 μm each. The experiments show very reproducible fatigue results with ductile failure behavior. The endurable stress amplitude decreases linearly with an increasing stress ratio, which can be displayed by a Smith diagram, even though the applied maximum stresses exceed the initial yield stresses determined by tensile tests. A scaling of the fatigue results by the tensile strength indicates that the fatigue level is significantly influenced by the strength of the material. Due to the very consistent findings, the development of a generalized fatigue model for predicting the lifetime of bonding wires with an arbitrary loading situation seems to be possible and will be further investigated.
Typically, plastic packaging materials are produced using additives, like e.g. stabilisers, to introduce specific desired properties into the material or, in case of stabilisers, to prolong the shelf life of such packaging materials. However, those stabilisers are typically fossil-based and can pose risks to both environmental and human health. Therefore, the present study presents more sustainable alternatives based on regional renewable resources which show the relevant antioxidant, antimicrobial and UV absorbing properties to successfully serve as a plastic stabiliser. In the study, all plants are extracted and characterised with regard to not only antioxidant, antimicrobial and UV absorbing effects, but also with regard to additional relevant information like chemical constituents, molar mass distribution, absorbance in the visible range et cetera. The extraction process is furthermore optimised and, where applicable, reasonable opportunities for waste valorisation are explored and analysed. Furthermore, interactions between analysed plant extracts are described and model films based on Poly-Lactic Acid are prepared, incorporating analysed plant extracts. Based on those model films, formulation tests and migration analysis according to EU legislation is conducted.
The well-known aromatic and medicinal plant thyme (Thymus vulgaris L.) includes phenolic terpenoids like thymol and carvacrol which have strong antioxidant, antimicrobial and UV absorbing effects. Analyses show that those effects can be used in both lipophilic and hydrophilic surroundings, that the variant Varico 3 is a more potent cultivar than other analysed thyme variants, and that a passive extraction setup can be used for extract preparation while distillation of the Essential Oils can be a more efficient approach.
Macromolecular antioxidant polyphenols, particularly proanthocyanidins, have been found in the seed coats of the European horse chestnut (Aesculus hippocastanum L.) which are regularly discarded in phytopharmaceutical industry. In this study, such effects and compounds have been reported for the first time while a valorisation of waste materials has been analysed successfully. Furthermore, a passive extraction setup for waste materials and whole seeds has been developed. In extracts of snowdrops, precisely Galanthus elwesii HOOK.F., high concentrations of tocopherol have been found which promote a particularly high antioxidant capacity in lipophilic surroundings. Different coniferous woods (Abies div., Picea div.) which are in use as Christmas trees are extracted after separating the biomass in leafs and wood parts before being analysed regarding extraction optimisation and drought resistance of active substances. Antioxidant and UV absorbing proanthocyanidins are found even in dried biomasses, allowing the circular use of already used Christmas trees as bio-based stabilisers and the production of sustainable paper as a byproduct.
While many proteins are known clients of heat shock protein 90 (Hsp90), it is unclear whether the transcription factor, thyroid hormone receptor beta (TRb), interacts with Hsp90 to control hormonal perception and signaling. Higher Hsp90 expression in mouse fibroblasts was elicited by the addition of triiodothyronine (T3). T3 bound to Hsp90 and enhanced adenosine triphosphate (ATP) binding of Hsp90 due to a specific binding site for T3, as identified by molecular docking experiments. The binding of TRb to Hsp90 was prevented by T3 or by the thyroid mimetic sobetirome. Purified recombinant TRb trapped Hsp90 from cell lysate or purified Hsp90 in pull-down experiments. The affinity of Hsp90 for TRb was 124 nM. Furthermore, T3 induced the release of bound TRb from Hsp90, which was shown by streptavidin-conjugated quantum dot (SAv-QD) masking assay. The data indicate that the T3 interaction with TRb and Hsp90 may be an amplifier of the cellular stress response by blocking Hsp90 activity.
Hydrogen‐Bonded Cholesteric Liquid Crystals—A Modular Approach Toward Responsive Photonic Materials
(2022)
A supramolecular approach for photonic materials based on hydrogen-bonded cholesteric liquid crystals is presented. The modular toolbox of low-molecular-weight hydrogen-bond donors and acceptors provides a simple route toward liquid crystalline materials with tailor-made thermal and photonic properties. Initial studies reveal broad application potential of the liquid crystalline thin films for chemo- and thermosensing. The chemosensing performance is based on the interruption of the intermolecular forces between the donor and acceptor moieties by interference with halogen-bond donors. Future studies will expand the scope of analytes and sensing in aqueous media. In addition, the implementation of the reported materials in additive manufacturing and printed photonic devices is planned.
Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.
Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.
When the Artemis missions launch, NASA's Orion spacecraft (and crew as of the Artemis II mission) will be exposed to the deep space radiation environment beyond the protection of Earth's magnetosphere. Hence, it is essential to characterize the effects of space radiation, microgravity, and the combination thereof on cells and organisms, i.e., to quantify any correlations between the deep space radiation environment, genetic variation, and induced genetic changes in cells. To address this, the Artemis I mission will include the Peristaltic Laboratory for Automated Science with Multigenerations (PLASM) hardware containing the Deep Space Radiation Genomics (DSRG) experiment. The scientific aims of DSRG are (i) to identify the metabolic and genomic pathways in yeast affected by microgravity, space radiation, and their combination, and (ii) to differentiate between gravity and radiation exposure on single-gene deletion/overexpressing strains' ability to thrive in the spaceflight environment. Yeast is used as a model system because 70% of its essential genes have a human homolog, and over half of these homologs can functionally replace their human counterpart. As part of the experiment preparation towards spaceflight, an Experiment Verification Test (EVT) was performed at the Kennedy Space Center to verify that the experiment design, hardware, and approach to automated operations will enable achieving the scientific aims. For the EVT, fluidic systems were assembled, sterilized, loaded, and acceptance-tested, and subsequently integrated with the engineering parts to produce a flight-like PLASM unit. Each fluidic system consisted of (i) a Media Bag, (ii) four Culture Bags loaded with Saccharomyces cerevisiae (two with deletion series and the remaining two with overexpression series), and (iii) tubing and check valves. The EVT PLASM unit was put under a temperature profile replicating the anticipated different phases of flight, including handover to launch, spaceflight, and splashdown to handover back to the science team, for a 58-day period. At EVT completion, the rate of activation, cellular growth, RNA integrity, and sample contamination were interrogated. All of the experiment's success criteria were satisfied, encouraging our efforts to perform this investigation on Artemis I. This manuscript thus describes the process of spaceflight experiment design maturation with a focus on the EVT, its results, DSRG's preparation for its planned launch on Artemis I in 2022, and how the PLASM hardware can enable other scientific goals on future Artemis missions and/or the Lunar Orbital Platform – Gateway.
(1) Background: Autologous bone is supposed to contain vital cells that might improve the osseointegration of dental implants. The aim of this study was to investigate particulate and filtered bone chips collected during oral surgery intervention with respect to their osteogenic potential and the extent of microbial contamination to evaluate its usefulness for jawbone reconstruction prior to implant placement. (2) Methods: Cortical and cortical-cancellous bone chip samples of 84 patients were collected. The stem cell character of outgrowing cells was characterized by expression of CD73, CD90 and CD105, followed by osteogenic differentiation. The degree of bacterial contamination was determined by Gram staining, catalase and oxidase tests and tests to evaluate the genera of the found bacteria (3) Results: Pre-surgical antibiotic treatment of the patients significantly increased viability of the collected bone chip cells. No significant difference in plasticity was observed between cells isolated from the cortical and cortical-cancellous bone chip samples. Thus, both types of bone tissue can be used for jawbone reconstruction. The osteogenic differentiation was independent of the quantity and quality of the detected microorganisms, which comprise the most common bacteria in the oral cavity. (4) Discussion: This study shows that the quality of bone chip-derived stem cells is independent of the donor site and the extent of present common microorganisms, highlighting autologous bone tissue, assessable without additional surgical intervention for the patient, as a useful material for dental implantology.
Telogene Einzelhaare sind häufig vorkommende Spurentypen an Tatorten. Derzeit werden sie zumeist von der STR-Typisierung ausgeschlossen, weil ihre STR-Profile aufgrund geringer DNA-Mengen und starker DNA-Degradierung in vielen Fällen unvollständig und schwierig zu interpretieren sind. In der vorliegenden Arbeit wurde eine systematische Vorgehensweise angewandt, um Korrelationen zwischen der DNA-Menge und DNA-Degradierung zu dem Erfolg der STR-Typisierung aufzuweisen und darauf basierend den Typisierungs-Erfolg von DNA aus Haaren vorhersagen zu können.
Zu diesem Zweck wurde ein human- (RiboD) und ein canin-spezifischer (RiboDog) qPCR-basierter Assay zur Messung der DNA-Menge und Bewertung der DNA-Integrität mittels eines Degradierungswerts (D-Wert) entwickelt. Aufgrund der Lage der genutzten Primer, welche auf ubiquitär vorkommende ribosomale DNA-Sequenzen abzielen, ist das Funktionsprinzip schnell und kostengünstig auf unterschiedliche Spezies anzuwenden. Die Funktionsweise der Assays wurde mittels seriell degradierter DNA bestätigt und der humane Assay wurde im Vergleich zum kommerziellen Quantifiler? Trio DNA Quantification Kit validiert. Schließlich wurde mit den Assays an DNA aus telogenen und katagenen Einzelhaaren von Menschen und Hunden der Zusammenhang zwischen DNA-Menge und DNA-Integrität zu der Vollständigkeit der STR-Allele (Allel Recovery) von DNA-Profilen untersucht, die mittels kapillarelektrophoretischer (CE) STR-Kits erhaltenen wurde. Es zeigte sich, dass bei humanen Einzelhaaren die Allel-Recovery sowohl von der DNA-Menge als auch der DNA-Integrität abhängt. Dagegen war die DNA-Degradierung bei einzelnen Hundehaaren durchweg geringer und die Allel-Recovery hing allein von der extrahierten DNA-Menge ab.
Um die STR-Analytik degradierter humaner DNA-Proben weiter zu verbessern, wurde ein neuartiger NGS-basierter Assay (maSTR, Mini-Amplikon-STR) etabliert, der die 16 forensischen STR-Loci des European Standard Sets und Amelogenin als sehr kurze Amplikons (76-296 bp) parallel amplifiziert. Mit intakter DNA generierte der maSTR-Assay im Mengenbereich von 200 pg eingesetzter DNA reproduzierbare, vollständige Profile ohne Allelic Drop-ins. Bei niedrigeren DNA-Mengen traten vereinzelt Allelic Drop-ins auf, wobei unter Verwendung von mindestens 43 pg DNA vollständige Profile erhalten wurden.
Die kombinierte Strategie aus RiboD-Messungen der DNA-Menge und -Integrität und daraus resultierendem STR-Typisierungserfolg des maSTR-Assays wurde an degradierter DNA validiert. Anschließend wurde die Strategie auf DNA aus telogenen und katagenen Einzelhaaren angewandt und mit den Ergebnissen des CE-basierten PowerPlex? ESX 17-Kits verglichen, das dasselbe STR-Marker-Set analysiert. Dabei zeigte sich, dass der Erfolg der STR-Typisierung beider STR-Assays sowohl von der optimalen Menge der Template-DNA als auch von der DNA-Integrität abhängt. Mit dem maSTR-Assay wurden vollständige Profile mit ungefähr 50 pg Input-DNA für leicht degradierte DNA aus Einzelhaaren nachgewiesen, sowie mit ungefähr 500 pg stark degradierter DNA. Aufgrund der geringen DNA-Mengen von telogenen Einzelhaaren schwankte die Reproduzierbarkeit der maSTR-Ergebnisse, war jedoch stets dem PowerPlex? ESX 17-Kit in Bezug auf die Allel-Recovery überlegen.
Ein Vergleich mit zwei, hinsichtlich der Längenverteilung der Amplikons komplementären CE-basierten STR-Kits (PowerPlex? ESX 17 und ESI 17 Fast), sowie mit einem kommerziellen NGS-Kit (ForenSeq? DNA Signature Prep) ergab, dass nicht die Technik der NGS, sondern die Kürze der Amplikons der wichtigste Faktor zur Typisierung degradierter DNA ist. Der maSTR-Assay wies in allen Vergleichen mit den genutzten kommerziellen Kits jedoch eine höhere Anzahl an Allelic Drop-ins auf. Diese traten umso häufiger auf, je geringer die verwendete DNA-Menge und je stärker degradiert diese war.
Weil Profile mit Allelic Drop-ins Mischprofilen entsprechen, wurden die per maSTR-Assay generierten STR-Profile mit Verfahren zur Interpretation von Mischspuren untersucht. Bei der Composite-Interpretation werden alle vorkommenden Allele von Replikaten gezählt, bei der Consensus-Interpretation lediglich die reproduzierbaren Allele. Dabei stellte sich heraus, dass im Fall von wenigen Allelic Drop-ins (PowerPlex? ESX 17-generierte Profile) die Composite-Interpretation und bei Allelic Drop-in-haltigen Profilen (maSTR-generierte Profile) die Consensus-Interpretation am besten geeignet ist.
Schließlich wurde mittels der GenoProof Mixture 3-Software untersucht, inwieweit semi- und vollständig kontinuierliche probabilistische Verfahren bei der biostatistischen Bewertung der DNA-Profile aus Einzelhaaren geeignet sind. Dabei zeigte sich, dass der maSTR-Assay aufgrund der hohen Anzahl an Allelic Drop-ins den CE-basierten Methoden nur in Fällen von DNA leicht überlegen ist, die in ausreichender Menge und gering degradiert vorliegt. In diesem Bereich gelingt die Zuordnung des Profils aus Haaren zum Referenzprofil jedoch ebenfalls mittels CE-basierten Methoden.
Aus allen Ergebnissen wurde eine Empfehlung für die Handhabung von DNA aus ausgefallenen Einzelhaaren abgeleitet, die auf dem DNA-Degradierungsgrad in Kombination mit der DNA-Menge basiert. Die vorliegende Arbeit schafft somit eine Grundlage, um ausgefallene Einzelhaare in der Routine-Arbeit von kriminaltechnischen Ermittlungen nutzbar zu machen, sowie gegebenenfalls auf andere Spurentypen mit degradierter DNA geringer Menge anzuwenden. Dadurch könnte die Nutzbarkeit solcher Spurentypen für die forensische Kriminalistik erhöht werden, insbesondere wenn die standardmäßig verwendeten CE-basierten Methoden versagen. Perspektivisch ist die Technik der NGS aufgrund der großen Multiplexierbarkeit uniformer, kurzer Marker generell der CE-basierten Technik bei der Typisierung degradierter DNA überlegen.
A main factor hampering life in space is represented by high atomic number nuclei and energy (HZE) ions that constitute about 1% of the galactic cosmic rays. In the frame of the “STARLIFE” project, we accessed the Heavy Ion Medical Accelerator (HIMAC) facility of the National Institute of Radiological Sciences (NIRS) in Chiba, Japan. By means of this facility, the extremophilic species Haloterrigena hispanica and Parageobacillus thermantarcticus were irradiated with high LET ions (i.e., Fe, Ar, and He ions) at doses corresponding to long permanence in the space environment. The survivability of HZE-treated cells depended upon either the storage time and the hydration state during irradiation; indeed, dry samples were shown to be more resistant than hydrated ones. With particular regard to spores of the species P. thermantarcticus, they were the most resistant to irradiation in a water medium: an analysis of the changes in their biochemical fingerprinting during irradiation showed that, below the survivability threshold, the spores undergo to a germination-like process, while for higher doses, inactivation takes place as a consequence of the concomitant release of the core’s content and a loss of integrity of the main cellular components. Overall, the results reported here suggest that the selected extremophilic microorganisms could serve as biological model for space simulation and/or real space condition exposure, since they showed good resistance to ionizing radiation exposure and were able to resume cellular growth after long-term storage.
Discrimination of Stressed and Non-Stressed Food-Related Bacteria Using Raman-Microspectroscopy
(2022)
As the identification of microorganisms becomes more significant in industry, so does the utilization of microspectroscopy and the development of effective chemometric models for data analysis and classification. Since only microorganisms cultivated under laboratory conditions can be identified, but they are exposed to a variety of stress factors, such as temperature differences, there is a demand for a method that can take these stress factors and the associated reactions of the bacteria into account. Therefore, bacterial stress reactions to lifetime conditions (regular treatment, 25 °C, HCl, 2-propanol, NaOH) and sampling conditions (cold sampling, desiccation, heat drying) were induced to explore the effects on Raman spectra in order to improve the chemometric models. As a result, in this study nine food-relevant bacteria were exposed to seven stress conditions in addition to routine cultivation as a control. Spectral alterations in lipids, polysaccharides, nucleic acids, and proteins were observed when compared to normal growth circumstances without stresses. Regardless of the involvement of several stress factors and storage times, a model for differentiating the analyzed microorganisms from genus down to strain level was developed. Classification of the independent training dataset at genus and species level for Escherichia coli and at strain level for the other food relevant microorganisms showed a classification rate of 97.6%.
Hydrophilic surface-enhanced Raman spectroscopy (SERS) substrates were prepared by a combination of TiO2-coatings of aluminium plates through a direct titanium tetraisopropoxide (TTIP) coating and drop coated by synthesised gold nanoparticles (AuNPs). Differences between the wettability of the untreated substrates, the slowly dried Ti(OH)4 substrates and calcinated as well as plasma treated TiO2 substrates were analysed by water contact angle (WCA) measurements. The hydrophilic behaviour of the developed substrates helped to improve the distribution of the AuNPs, which reflects in overall higher lateral SERS enhancement. Surface enhancement of the substrates was tested with target molecule rhodamine 6G (R6G) and a fibre-coupled 638 nm Raman spectrometer. Additionally, the morphology of the substrates was characterised using scanning electron microscopy (SEM) and Raman microscopy. The studies showed a reduced influence of the coffee ring effect on the particle distribution, resulting in a more broadly distributed edge region, which increased the spatial reproducibility of the measured SERS signal in the surface-enhanced Raman mapping measurements on mm scale.
Composite nanoparticles (NPs) consisting of lignin and different polysaccharide (PS) derivatives were prepared. In this synergistic approach, the PS derivative acts as biocompatible matrix that forms spherical NPs while lignin is a functional compound with therapeutic potential (e.g., antioxidative, antimicrobial, antiviral). Organosolv lignin and three different PS derivatives (cellulose acetate/CA, cellulose acetate phthalate/CAPh, xylan phenyl carbonate/XPC) were used in this study. Nanocomposites with particle sizes in the range of about 200–550 nm containing both types of biopolymers are accessible by dialysis of organic PS/lignin solutions against water. In particular, XPC and CAPh, which both contain aromatic substituents, were found to be suitable for incorporation of lignin within the PS nanomatrix. The present work paves the way for future studies in which the pharmaceutical potential and biocompatibility of composite NPs of lignin and PS derivatives with tailored properties are investigated.
There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of 13C-propionate (exhaled 13CO2), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.
The white ground crater by the Phiale Painter (450–440 BC) exhibited in the “Pietro Griffo” Archaeological Museum in Agrigento (Italy) depicts two scenes from Perseus myth. The vase is of utmost importance to archaeologists because the figures are drawn on a white background with remarkable daintiness and attention to detail. Notwithstanding the white ground ceramics being well documented from an archaeological and historical point of view, doubts concerning the compositions of pigments and binders and the production technique are still unsolved. This kind of vase is a valuable rarity, the use of which is documented in elitist funeral rituals. The study aims to investigate the constituent materials and the execution technique of this magnificent crater. The investigation was carried out using non-destructive and non-invasive techniques in situ. Portable X-ray fluorescence and Fourier-transform total reflection infrared spectroscopy complemented the use of visible and ultraviolet light photography to get an overview and specific information on the vase. The XRF data were used to produce false colour maps showing the location of the various elements detected, using the program SmART_scan. The use of gypsum as the material for the white ground is an important result that deserves to be further investigated in similar vases.
Cytokine-induced killer cells (CIK) in combination with dendritic cells (DCs) have shown favorable outcomes in renal cell carcinoma (RCC), yet some patients exhibit recurrence or no response to this therapy. In a broader perspective, enhancing the antitumor response of DC-CIK cells may help to address this issue. Considering this, herein, we investigated the effect of anti-CD40 and anti-CTLA-4 antibodies on the antitumor response of DC-CIK cells against RCC cell lines. Our analysis showed that, a) anti-CD40 antibody (G28.5) increased the CD3+CD56+ effector cells of CIK cells by promoting the maturation and activation of DCs, b) G28.5 also increased CTLA-4 expression in CIK cells via DCs, but the increase could be hindered by the CTLA-4 inhibitor (ipilimumab), c) adding ipilimumab was also able to significantly increase the proportion of CD3+CD56+ cells in DC-CIK cells, d) anti-CD40 antibodies predominated over anti-CTLA-4 antibodies for cytotoxicity, apoptotic effect and IFN-g secretion of DC-CIK cells against RCC cells, e) after ipilimumab treatment, the population of Tregs in CIK cells remained unaffected, but ipilimumab combined with G28.5 significantly reduced the expression of CD28 in CIK cells. Taken together, we suggest that the agonistic anti-CD40 antibody rather than CTLA-4 inhibitor may improve the antitumor response of DC-CIK cells, particularly in RCC. In addition, we pointed towards the yet to be known contribution of CD28 in the crosstalk between anti-CTLA-4 and CIK cells.
The human enzymes GLYAT (glycine N-acyltransferase), GLYATL1 (glutamine N-phenylacetyltransferase) and GLYATL2 (glycine N-acyltransferase-like protein 2) are not only important in the detoxification of xenobiotics via the human liver, but are also involved in the elimination of acyl residues that accumulate in the form of their coenzyme A (coA) esters in some rare inborn errors of metabolism. This concerns, for example, disorders in the degradation of branched-chain amino acids, such as isovaleric acidemia or propionic acidemia. In addition, they also assist in the elimination of ammonium, which is produced during the transamination of amino acids and accumulates in urea cycle defects. Sequence variants of the enzymes have also been investigated, which may provide evidence of impaired enzyme activities, from which therapy adjustments can potentially be derived. A modified Escherichia coli strain was chosen for the overexpression and partial biochemical characterization of the enzymes, which may allow solubility and proper folding. Since post-translational protein modifications are very limited in bacteria, we also attempted to overexpress the enzymes in HEK293 cells (human-derived). In addition to characterization via immunoblots and activity assays, intracellular localization of the enzymes was also performed using GFP coupling and confocal laser scanning microscopy in transfected HEK293 cells. The GLYATL2 enzyme may have tasks beyond detoxification and metabolic defects and the preliminary molecular biology work has been performed as part of this project - the enzyme activity determinations were outsourced to a co-supervised bachelor thesis. The enzyme activity determinations with purified recombinant human enzyme from Escherichia coli provided a threefold higher activity of the sequence variant p.(Asn156Ser) for GLYAT, which should be considered as the probably authentic wild type of the enzyme. In addition, a reduced activity of the GLYAT variant p.(Gln61Leu), which is very common in South Africa, was shown, which could be of particular importance in the treatment of isovaleric acidemia, which is also common in South Africa. Intracellularly, GLYAT and GLYATL1 could be localized mitochondrially. As the analyses have shown, sequence variations of GLYAT and GLYATL1 influence their enzyme activity. As an example, the GLYAT variant p.(Gln61Leu) is frequently found in South Africa. In the case of reduced GLYAT activity, patients could be increasingly treated with L-carnitine in the sense of an individualized therapy, since the conjugation of the toxic isovaleryl-coA with glycine is restricted by the GLYAT sequence variation. Activity-reducing variants identified in this project are of particular interest, as they may influence the treatment of certain metabolic defects.
The following work presents algorithms for semi-automatic validation, feature extraction and ranking of time series measurements acquired from MOX gas sensors. Semi-automatic measurement validation is accomplished by extending established curve similarity algorithms with a slope-based signature calculation. Furthermore, a feature-based ranking metric is introduced. It allows for individual prioritization of each feature and can be used to find the best performing sensors regarding multiple research questions. Finally, the functionality of the algorithms, as well as the developed software suite, are demonstrated with an exemplary scenario, illustrating how to find the most power-efficient MOX gas sensor in a data set collected during an extensive screening consisting of 16,320 measurements, all taken with different sensors at various temperatures and analytes.
Jet engines of airplanes are designed such that in some components damage occurs and accumulates in service without being critical up to a certain level of damage. Since maintenance, repair, and component exchange are very cost-intensive, it is necessary to predict efficiently the component lifetime with high accuracy. A former developed lifetime model, based on interpolated results of aerodynamic and structural mechanics simulations, uses material parameters estimated from literature values of standard creep experiments. For improved accuracy, an experimental procedure is developed for the characterization of the short-time creep behavior, which is relevant for the operation of turbine blades of jet engines. To consider microstructural influences resulting from the manufacturing of thin-walled single crystal turbine blades, small-scale specimens from used turbine blades are extracted and tested in short- and medium-time creep experiments. Based on experimental results and literature values, a creep model, which describes the fracture behavior for a wide range of creep loads, is calibrated and is now used for the lifetime prediction of turbine blades under real loading conditions.
With the increasing demand for ultrapure water in the pharmaceutical and semiconductor industry, the need for precise measuring instruments for those applications is also growing. One critical parameter of water quality is the amount of total organic carbon (TOC). This work presents a system that uses the advantage of the increased oxidation power achieved with UV/O3 advanced oxidation process (AOP) for TOC measurement in combination with a significant miniaturization compared to the state of the art. The miniaturization is achieved by using polymer-electrolyte membrane (PEM) electrolysis cells for ozone generation in combination with UV-LEDs for irradiation of the measuring solution, as both components are significantly smaller than standard equipment. Conductivity measurement after oxidation is the measuring principle and measurements were carried out in the TOC range between 10 and 1000 ppb TOC. The suitability of the system for TOC measurement is demonstrated using the oxidation by ozonation combined with UV irradiation of defined concentrations of isopropyl alcohol (IPA).
Background: Cancer heterogeneity poses a serious challenge concerning the toxicity and adverse effects of therapeutic inhibitors, especially when it comes to combinatorial therapies that involve multiple targeted inhibitors. In particular, in non-small cell lung cancer (NSCLC), a number of studies have reported synergistic effects of drug combinations in the preclinical models, while they were only partially successful in the clinical setup, suggesting those alternative clinical strategies (with genetic background and immune response) should be considered. Herein, we investigated the antitumor effect
of cytokine-induced killer (CIK) cells in combination with ALK and PD-1 inhibitors in vitro on genetically variable NSCLC cell lines.
Methods: We co-cultured the three genetically different NSCLC cell lines NCI-H2228 (EML4-ALK), A549 (KRAS mutation), and HCC-78 (ROS1 rearrangement) with and without nivolumab (PD-1 inhibitor) and crizotinib (ALK inhibitor). Additionally, we profiled the variability of surface expression multiple immune checkpoints, the concentration of absolute dead cells, intracellular granzyme B on CIK cells using flow cytometry as well as RT-qPCR. ELISA and Western blot were performed to verify the activation of CIK cells.
Results: Our analysis showed that (a) nivolumab significantly weakened PD-1 surface expression on CIK cells without impacting other immune checkpoints or PD-1 mRNA expression, (b) this combination strategy showed an effective response on cell viability, IFN-g production, and intracellular release of granzyme B in CD3+ CD56+ CIK cells, but solely in NCI-H2228, (c) the intrinsic expression of Fas ligand (FasL) as a T-cell activation marker in CIK cells was upregulated by this additive effect, and (d) nivolumab induced Foxp3 expression in CD4+CD25+ subpopulation of CIK cells significantly increased. Taken together, we could show that CIK cells in combination with crizotinib and nivolumab can enhance the anti-tumor immune response through FasL activation, leading to increased IFN-g and granzyme B, but only in NCI-H2228 cells with EML4-ALK rearrangement. Therefore, we hypothesize that CIK therapy may be a potential alternative in NSCLC patients harboring EML4-ALK rearrangement, in addition, we support the idea that combination therapies offer significant potential when they are optimized on a patient-by-patient basis.