Physiological Activities of Adiponectin Provide Therapeutic Opportunities in Sepsis

Sepsis represents a life-threatening organ dysfunction due to a compromised host response caused by bacterial and viral infections. Although progress has been made to unravel the underlying pathophysiology, sepsis remains a very serious condition. Adiponectin is an adipokine with multiple beneficial activities relevant to glucose and lipid metabolism whose serum levels are low in obesity and metabolic diseases. In addition, several immunoregulatory activities of adiponectin have been described and circulating adiponectin levels have been positively associated with inflammation in autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. Although an understanding of physiological consequences is still limited, blood adiponectin levels are also elevated in chronic kidney disease and liver cirrhosis, possibly due to impaired biliary and renal excretion. Natriuretic peptides, which increase adiponectin synthesis in adipocytes and are induced in autoimmune diseases and cirrhosis and decreased in obesity, appear to contribute to altered systemic adiponectin levels. In patients with sepsis, data on circulating adiponectin levels are not concordant, probably due to the large diversity in cohorts analyzed, often including patients with a higher risk for severe sepsis due to chronic metabolic disease or other comorbidities. This review article summarizes the main physiological activities of adiponectin and describes its role in inflammation and experimental sepsis. Adiponectin levels obtained in observational studies from serum or plasma of patients with critical illness are discussed. From this analysis, we conclude that circulating adiponectin levels are reduced in sepsis and septic shock, suggesting the potential of adiponectin receptor agonists as an option for sepsis therapy

Nucleophilic Functionalization of a Cationic Pentaphosphole Complex–A Systematic Study of Reactivity

The systematic nucleophilic functionalization of the cationic pentaphosphole ligand complex [Cp*Fe(η4-P5Me)][OTf] (A) with group 16/17 nucleophiles is reported. This method represents a highly reliable and versatile strategy for the design of novel transition-metal complexes featuring twofold substituted end-deck cyclo-P5 ligands, bearing unprecedented hetero-element substituents. By the reaction of A with classical group 16 nucleophiles, complexes of the type [Cp*Fe(η4-P5MeE)] (E=OEt (1), OtBu (2), SPh (3), SePh (4)) are obtained. By transferring this protocol to group 17 nucleophiles, the highly sensitive complexes [Cp*FeP5(η4-P5MeX)] (X=F (5), Cl (6), Br (7), I (8)) could be isolated. All products show exclusively 1,1'-substitution at the cyclo-P5 ring. Interestingly, further studies on the reactivity of the halogenated species revealed their ability to undergo ring-opening reactions with cyclic ethers such as THF and ethylene oxide yielding [Cp*FeP5(η4-P5MeOC4H8X)] (X=Br (9), I (10)) or [Cp*FeP5(η4-P5MeOC2H4X)] (X=Br (11), I (12)), respectively. Furthermore, the use of acyclic ethers such as dimethoxyethane led to the formation of [Cp*FeP5(η4-P5MeOC2H4OCH3)] (13) mediated by C−O bond cleavage, followed by subsequent P−O bond formation, as further enlightened by DFT calculations

Performancevergleich von Luxusuhren, Oldtimern und Wein

Ergänzend zu den Studien Köstlmeier/Röder in CF 2022, CF 2023 und CF 2024 werden die Preisentwicklungen des globalen Markts für Oldtimer von Dez. 2003 bis März 2024 analysiert. Mit einer Rendite von 7,75% p.a. und einem geringen Maximum Drawdown von -3,94% schneiden Oldtimer im Vergleich zu einem Weltmarktportfolio (6,06%, -38,55%) und Aktien (DAX: 7,90%, -52,35%) solide ab. In einer zweiten Zeitreihe von Dez. 2010 bis Dez. 2021 wird die Performance des bereits bekannten Watch30-Index (7,98% p.a.) mit der Wertentwicklung von Oldtimern (7,25%) und Wein (1,60%) verglichen. Eine Korrelationsanalyse deutet potenzielle Diversifikationsvorteile an. In Zusammenhang mit positiver Schiefe und geringem Maximum-Drawdown könnten sich somit für Luxusuhren und Oldtimer attraktive Renditechancen für Investoren bei nur begrenztem Verlustrisiko bei diversifizierten Anlagen zeigen

Small Inorganic Ring Systems: Understanding Cyclization and Bond Activation Processes

Within this work, the modification of the substituents at silicon of heterocyclic four-membered silyl phosphonium ions was investigated. In chapter 1 a general overview of the current state of research, and the design principles, to which the structure of the four-membered phosphonium ions adhere, are presented. The focus of chapter 3 is the modification of previously known silyl phosphine chalcogenides with different substituents and Lewis basic chalcogenides. New synthesis routes towards these novel compounds were developed, the structures synthesized and thoroughly investigated by means of single-crystal X-ray diffraction analysis, NMR analysis and DFT calculations. Through this procedure a deep understanding of the governing principles of steric and electronic effects within these four-membered silyl phosphonium chalcogenides was obtained. When all substituents are replaced by sterically demanding tert-butyl substituents, the choice of chalcogen used as a Lewis base becomes crucial for successful ring formation. The angular strain within the four-membered rings was found to be well balanced in all four-membered CPChSi rings investigated. Thermochemical investigations showed that the substituents on the silicon and phosphorus atoms play an important role for the strength of the intramolecular Ch–Si coordination. In the absence of large steric repulsions through bulky substituents (methyl groups on silicon, tert-butyl groups on phosphorus), a stability sequence depending on the chalcogen atom in the direction Se ≤ S < O can be observed. However, the order is reversed (O < S < Se) in case of strong repulsions between sterically demanding substituents (tert-butyl groups on both silicon and phosphorus atoms). Due to the shorter Si–O bond length compared to the Si–S and Si–Se bond lengths, the substituents of the phosphorus and silicon atom are forced in closer proximity in the four-membered cations. In the case of all-tert-butyl substituted compound I this leads to a significant increase in steric repulsion in this cation, therefore hampering its synthesis. Building upon this knowledge, another second-row element, nitrogen, was investigated as a donor in chapter 4. The nitrogen atom was introduced as a phosphinimine moiety into the systems. In contrast to phosphine chalcogenides, phosphinimine donor moieties allow for further modification of donor strength by the influence of steric or electronic parameters. The introduction of either a trimethylsilyl or a bis(3,5-trifluoromethylphenyl)boryl moiety allows for additional ring strain in these systems. Furthermore, an electronic destabilization of the Si–N bond was expected to be achieved by either resonance stabilization by the bis(3,5-trifluoromethylphenyl)boryl moiety or by hyperconjugative n(N)→σ*(SiMe) interactions from the –SiMe3 moiety. Taken together, these effects are expected to facilitate ring opening and enable small molecule activation or even catalytic transformations. The rational synthesis of these systems, the influence of steric and electronic factors, and the reactivity in terms of catalytic applications and FLP-like behavior were investigated. The silylated phosphinimines can be easily obtained in moderate to good yields. The ring-closure reactions of the methyl- and iso-propyl-substituted silanes (X, XI) proceeded smoothly, however the case of the all tert-butyl substituted silyl phosphinimine IX no ring closure was possible. Like the P–O bond length [1.4958(8) Å] in compound I the P–N bond length [1.538(2) Å] in compound IX is also very short, therefore the same effects hampering the ring formation in compound I were found to also affect the ring formation in compound IX. The Si–N bonds in the SiMe3-substituted four-membered phosphonium ions XII[B(C6F5)4] and XIII[B(C6F5)4] were found to be covalent in nature, and did not possess the ability to reversibly open as anticipated. Nevertheless, we were able to gain valuable insights from these results and therefore we set out to design a new system with a maximum of steric hinderance, while also preserving the desired ability to remove the hydride from the Si¬–H moiety. Therefore, an electrophilic boryl moiety was introduced to study the effect of electron-withdrawing groups on the reversible opening ability of these ring systems. With the zwitterionic compound XIV reversibility was finally achieved which was evidenced by the ability of compound XIV to catalyze the hydrosilylation of nitriles. This validated our approach of combining steric and electronic factors to weaken the Si¬–N bond in compound XIV. Upon receiving preliminary confirmation through this experiment, that reversibility is in principle possible within these systems our attention shifted away from the strongly Lewis acidic silylium-based Lewis acids towards neutral silicon-based Lewis acids. The rational was, that neutral silicon-based Lewis acids are of lower Lewis acidity compared to silylium ions, and therefore reversibility within these systems can be easier achieved. The question whether this really is the case was addressed in chapter 5. Several novel neutral Lewis acidic silanes were prepared and incorporated within the previously described CPSSi cycles (chapter 3). By varying the electron-withdrawing groups from pentafluorophenyl [-C6F5] over pentafluorophenoxy [-OC6F5] to tetrafluorocatecholato [-O2C6F4] moieties, a discernible difference in Lewis acidity at the silicon center was observed (Scheme 8.3). While the pentafluorophenyl [-C6F5] substituted compound showed no Lewis acidity, the tetrafluorocatecholato [-O2C6F4] substituted silane was strongly prone towards formation of the pentacoordinate state making the desired Si–H substituted tetravalent silane inaccessible. A good balance between Lewis acidity and stability of the tetravalent state was found with the pentafluorophenoxy [-OC6F5] substituted compound XV. Through in depth NMR spectroscopic experiments a equilibrium between compounds XV and XVI could be observed. Compound XV represents an intriguing structure as it combines a highly reducing anionic Si–H function, aswell as a protic cationic N–H function in close proximity to each other. To the best of our knowledge this is the only example were both motifs can be found within one molecule. Through additional time resolved NMR experiments it was also found that compound XV is not stable over a prolonged amount of time and slowly reacts with the loss of dihydrogen towards compound XVII. In conclusion the introduction of neutral Lewis acidic silanes indeed proved to ease the ability of the silicon Lewis acids to reversibly attach to Lewis bases. In a second part of this doctoral project, chiral silanethiols were synthesized and investigated as enantioselective hydrogen-atom transfer (HAT) catalysts together with the group of Prof. König. The deracemization was achieved by a sequence of photocatalytic hydrogen-atom transfer, reductive radical-polar crossover (RRPCO), and protonation. Our goal was to design silanethiols which were able to act as potent and enantioselective HAT-catalysts. To achieve this goal, different strategies were employed. The first attempt was made with a silanethiol which was equipped with chiral substituents. Therefore the (–)-menthol substituted silanethiol XVIII was prepared and tested, and while compound XVIII performed well as a HAT-catalysts no enantioselectivity was observed. Next, the Si-chiral silanethiol XIX was prepared and tested. The idea was to bring the chiral information closer to the reactive Si¬–S– function, and therefore enhance enantioselectivity. This approach was successful and compound XIX performed well as a HAT catalyst and gave an enantiomeric excess of 16 % in the final product. While this finding served as proof that chiral silanethiols can indeed be used as enantioselective HAT-catalysts, the enantiomeric excess obtained was not good enough for practical use. In order to increase the enantioselectivity even further, the successful concept of using Si-chiral silanethiols was combined with a chiral backbone. A suitable motif, which combined both desired features was found in a class of silanthiols with a ferrocene backbone [(SSi,SP)-XX and (SSi,SP)-XXI]. While both compounds are Si-stereogenic, they also exhibit planar chirality in the ferrocenyl backbone. However, when employing compounds (SSi,SP)-XX and (SSi,SP)-XXI in the RRPCO-HAT-protonation sequence, decomposition was observed. No catalytic activity nor enantioselectivity was observed for both compounds, therefore concluding that the ferrocene backbone is not suitable for this application. In summary, this lays the foundation for the design of silanethiol HAT catalysts based on the general structure of compound XIX

Unconventional Josephson supercurrent diode effect induced by chiral spin-orbit coupling

Chiral materials lacking mirror symmetry can exhibit unconventional spin-orbit fields, including fully momentum-aligned radial Rashba fields as seen in twisted van der Waals homobilayers. We theoretically study Cooper-pair transfer in superconductor/ferromagnet/superconductor Josephson junctions with crossed (tangential and radial) interfacial Rashba fields. We find that their interplay leads to what we call the unconventional supercurrent diode effect (SDE), where supercurrent rectification occurs even with collinear (with respect to the current) barrier magnetization, not possible for conventional spin-orbit fields. This SDE, distinct from conventional Rashba-induced effects on Cooper-pair momenta, arises from the spin precession in the magnetic barrier. We propose it as a sensitive probe of chiral spin textures

Aufbau eines Modellsystems zur Untersuchung strömungsinduzierter Akkumulation plasmatischer Proteine

Im Rahmen von ECMO-Therapien stellen Blutungen und thrombotische Ereignisse ein noch unzureichend geklärtes Problem dar. Im Membranoxygenator entstehende thrombotische Ablagerungen bedingen dabei mitunter den Austausch des Oxygenators auf Grund einer eingeschränkten Gasaustauschkapazität. Die Konstruktion eines miniaturisierten ECMO-Modells soll eine genauere Aufschlüsselung der ablaufenden Gerinnungsprozesse an ECMO-Oxygenatorbestandteilen ermöglichen. Dazu erfolgte die Inbetriebnahme einer Pumpe mit in den Strömungskanal integrierten ECMO-Bestandteilen. Das betriebene Pumpenmodell wurde im Hinblick auf die angewandten Strömungseigenschaften und die Versuchskompatibilität untersucht. Unter Anwendung von Live-Cell-Imaging wurden an senkrecht in einer Flusskammer befindlichen Oxygenatorfasern Klotablagerungen aus bewegtem Blutplasma erzeugt. Fluoreszenzmikroskopische Analysen konnten keinen sicheren Nachweis von von-Willebrand-Faktor als Klotbestandteil erbringen. Die Klotbildung konnte trotz vorhandener Citratantikoagulation des Blutplasmas nachverfolgt werden. Die genaue Zusammensetzung des Klots bedarf weiterführender Untersuchungen

Developing Novel Functional Laser-Induced Carbon Nanofibers for Miniaturized Electroanalytical Biosensors

Electrochemical sensors are ideal candidates for point-of-care diagnostics due to their low cost, sensitivity, and direct data readout. Nowadays, enzyme-based sensors dominate the electrochemical diagnostics market due to their outstanding selectivity. However, there are some drawbacks related to the use of enzyme like stability issues or high manufacturing costs. This thesis highlights the need for enzyme-free alternatives and provides a comprehensive overview of non-enzymatic sensors and their development. The definition, principles, and typical detection mechanisms of electrochemical sensing are explained. Various conventional strategies for fabricating enzyme-free electrochemical sensors, such as drop-casting, dip-coating, electro- and electroless deposition, screen/inkjet/3D-/roll-to-roll printing, and the emerging technology of laser scribing, are introduced and compared in terms of cost, complexity, mass production capability, and their individual pros and cons. Additionally, considerations regarding selectivity, sensitivity, and biofouling when applying these sensors to different matrices, such as clinical samples (blood, dermal interstitial fluid, sweat, saliva, urine, breath) and non-clinical samples (water from rivers, lakes, seas, food and beverages, cell culture media), are presented. Other challenges and potential solutions related to electrode fouling, measurements under physiological conditions, biocompatibility, long-term stability, storage, practical issues, and efficiency are also discussed. In this thesis, a non-enzymatic electrochemical sensor based on laser-induced carbon nanofibers (LCNFs) for detecting hydrogen peroxide was developed. The working electrode was laser-scribed on polyimide nanofibers produced by electrospinning. These fibers contained either one or a mixture of both metal salts Pt(II)- and Ni(II)-acetylacetonate, which were converted to nanoparticles embedded within the LCNF during the laser treatment. The resulting nanoparticles consisted either of Pt- or Ni- metals and their oxides, or Pt-Ni-alloyed metal and its oxide in the case of a mixture. In the measurement setup, a Pt-wire and an Ag/AgCl electrode were used as the counter and reference electrodes, respectively, to investigate hydrogen peroxide detection. LCNFs with various compositions of the metal salts were tested towards the catalytic behavior to hydrogen peroxide and their selectivity. The best sensitivity (with a limit of detection (LOD) of 1.4 ± 0.4 μM) in an un-stirred approach was achieved by oxidizing hydrogen peroxide on a pure Pt-LCNF, but this led to unsatisfactory selectivity. Strategies such as increasing the metal content or using polymer coatings were applied to improve selectivity. Drop-coating the electrode with nylon also improved the recovery of hydrogen peroxide spiked in real matrices (undiluted and diluted human serum). Selectivity was further improved by reducing the measurement potential and switching from oxidation to reduction of hydrogen peroxide, although this came at the cost of sensitivity. Additionally, strategies to attach polyoxometalates as alternative catalysts onto the LCNF surface were explored but did not result in sensitive hydrogen peroxide detection. A second project in this thesis focused on the non-enzymatic electrochemical detection of glucose under physiological conditions. It is well-known that glucose oxidation is catalyzed on Ni-surfaces at an alkaline pH. Therefore, the Pt/Ni-alloyed LCNF described in the previous project was used to efficiently generate a high local pH by an electrochemical pretreatment (-0.9 V for 20 s) on the Pt-sites of the LCNF, enabling glucose measurement on the Ni-sites of the alloy in a consecutive cyclovoltammetry measurement, even though the initial pH of the solution was 7.4. To enable long-term measurements, an electrochemical treatment after each measurement was introduced to clean the catalyst surface. After optimizing (i) the pretreatment, (ii) the catalyst cleaning, (iii) the measurement conditions, and (iv) the data treatment, glucose could be selectively detected in physiologically relevant concentrations with a LOD of 0.3 ± 0.1 mM. Furthermore, the aging of the electrode was investigated, where hydrophobicity is increasing with time, leading to a reduced contact between electrode and solution. To resolve this, a simple Tween-20 incubation was applied prior to measurement. Finally, the electrode performance was not affected after sterilization, and a recovery of 95 ± 10% in spiked, diluted human serum was achieved. In the last project, pure Ni-LCNF were laser-scribed as a 3-electrode system (LCNF was used as the working, counter, and reference electrode) and used to detect glucose in simulated breath. Glucose solutions with concentrations similar to those present in lung fluids were nebulized, captured on the porous LCNFs, and electrochemically measured in NaOH solution. With optimized manufacturing, glucose-capturing, and measurement parameters, glucose was detected selectively using cyclovoltammetry and a ratiometric data readout. To simulate variations in lung fluid concentration (reflecting blood sugar level variations), various glucose concentrations of the nebulized solutions were captured, measured, and could be distinguished from each other

Digital Forensics Readiness for the Internet of Things

The Internet of Things (IoT) is becoming an integral part of daily life, transforming both personal and business practices. From a Digital Forensics (DF) perspective, IoT environments offer valuable evidence and diverse artifacts that can significantly assist in- vestigations. Therefore, DF must adapt to the unique characteristics of IoT environments. As IoT deployment increases, organizations must rethink their planning, development, and implementation of Information Technology (IT) security strategies. While the IoT opens new business opportunities, it also introduces various challenges related to cyber- attacks and their mitigation. In this regard, Forensics Readiness (FR) can help balance the cost of investigating future incidents by preparing for them. To research Internet of Things Forensics Readiness (IoT-FR) from a holistic perspective, it is essential to consider the human aspect (e.g., include investigators and non-experts), the process aspect (e.g., enable structured integration), and the technical aspect (e.g., consider IoT conditions). Thus, the threefold dissertation first explores how awareness and education can support DF within IoT environments, indicating a shift towards applying gamification elements and serious games. Secondly, this research work highlights the importance of processes that help to structure DF investigations in IoT to enable FR in the first place by extracting influencing factors and helping investigators in tool decision and application. Thirdly, the dissertation explores the IoTs unique technical circumstances that require novel and updated DF approaches and shows the potential of utilizing technological developments to support the technical investigation. The research progress in IoT-FR lays a robust foundation for integrating and realizing FR in IoT environments in the future. This enables, at the same time, the design of secure systems through new insights gained from sustainable and comprehensive Internet of Things Forensics (IoTF) investigations

Randomized clinical split-mouth study on a self-adhesive vs. a conventional bulk-fill composite in class II cavities: Results after five years

Aim In this randomized prospective split-mouth study, the clinical survival and performance of a novel not yet commercially available self-adhesive dual-curing bulk-fill restorative material (SA, Solventum) and a conventional bulk-fill composite (Filtek One, Solventum; FO) were examined for restoration of class II cavities over a period of 60 months. Methods 30 patients underwent the placement of one SA and one FO restoration each. FO restorations were bonded using Scotchbond Universal (Solventum) in self-etch mode, while SA was applied without adhesive. This publication reports restoration survival as a primary outcome and quality parameters of restorations according to FDI criteria as a secondary outcome at baseline, 48 and 60 months. Restorations were evaluated by two independent examiners. Kaplan-Meier survival analysis and non-parametric statistical methods were employed (χ2-tests; α=0.05).The study was registered prior to commencement (German Register of Clinical Studies: DRKS00013564). Results 25 patients out of initially 30 were available at 60-mo recall. At 60-mo, FO exhibited a clinical survival rate of 97.1 % and SA of 98.9 % without significant difference (p > 0.05). All restorations available for clinical evaluation maintained clinically acceptable FDI scores throughout the follow-up period. FO significantly outperformed SA in terms of surface luster, color match and translucency at both evaluation time points, in terms of marginal staining at 60-mo and in terms of surface staining at 48-mo. Surface luster, surface staining and marginal adaptation deteriorated over time for both materials. Conclusions Both materials demonstrated similar clinical survival and performance over 60 months, which is to date the longest observation period for a clinical study including a self-adhesive bulk-fill restorative. SA displayed slightly inferior but clinically acceptable esthetic properties compared to FO. Both materials exhibited clinically acceptable outcomes over 60 months, warranting their recommendation for clinical use. Clinical Significance The novel self-adhesive dual-curing bulk-fill restorative material exhibited clinically acceptable outcomes over 60 months, similarly to a conventional bulk-fill restorative used with a universal adhesive, with only minor cutbacks in esthetic properties. Thus, both materials can be considered suitable for clinical application

Visualizing Standing Light Waves in Continuous-Beam Transmission Electron Microscopy

The phase-resolved imaging of confined light fields by homodyne detection is a cornerstone of metrology in nanooptics and photonics, but its application in electron microscopy has been limited so far. Here, we report the mapping of optical modes in a waveguide structure by illumination with femtosecond light pulses in a continuous-beam transmission electron microscope. Multiphoton photoemission results in a remanent charging pattern which we image by Lorentz microscopy. The resulting image contrast is linked to the intensity distribution of the standing light wave and is quantitatively described within an analytical model. The robustness of the approach is showcased in a wider parameter range and more complex sample geometries including micro- and nanostructures. We discuss further applications of light-interference- based charging for electron microscopy with in situ optical excitation, laying the foundation for advanced measurement schemes for the phase-resolved imaging of propagating light fields