Showing papers by "Saarland University published in 2023"

Halogen‐bonded Liquid Crystals

Abstract: While the halogen bond has been recognised and studied for over a hundred years, it is only in more recent times that chemists have begun to apply it and see its possibilities as another supramolecular interaction that can be deployed in the preparation of materials. This review takes one of those areas, liquid crystals, and considers examples of motifs that have been deployed successfully to generate new mesogens. In particular, rather than attempting to be comprehensive, the article reviews critically data from well-characterised systems and seeks to first make some comparisons with analogous hydrogen-bonded materials, before considering how the lability and flexibility of the halogen bond expresses itself in liquid crystal behaviour.

Landschaft – eine theoretische Einordnung

Abstract: Der Beitrag basiert auf einer Gliederung von drei Landschaften, die sich aus der Drei-Welten-Theorie Karl Poppers ableitet. Die Zahl der theoretischen Perspektiven auf Landschaft hat in den vergangenen Jahrzehnten rasch zugenommen. Damit hat sich die Landschaftsforschung sukzessive von den Wurzeln einer essentialisierenden ‚Landeskunde‘ entfernt und ist an aktuelle Diskurse der sozial- und kulturwissenschaftlichen Landschaftsforschung anschlussfähig geworden. Wenngleich bis heute in der naturwissenschaftlichen Landschaftsforschung ein positivistisches Verständnis von Landschaft (1) im Sinne eines materiellen Gegenstandes vorherrscht, hat sich in der sozialwissenschaftlichen Forschung ein Kanon konstruktivistischer Perspektiven entwickelt, die soziale Konstruktionsprozesse von Landschaft (3) für konstitutiv für Landschaft halten. ‚More-than-Representational-Ansätze‘ versuchen diese Dualität aufzulösen, wenn etwa Landschaft 2 (Landschaft des Individuums) und sein Erleben von Landschaft 1 in das Zentrum des Interesses der phänomenologischen Landschaftsforschung rückt. Infolge der begrenzten Deutungsumfänge der unterschiedlichen Theorien für den komplexen Gegenstand ‚Landschaft‘, schlägt die neopragmatische Landschaftsforschung vor, abgewogen und begründet Theorien, Methoden, Daten und Forschendenperspektiven zu triangulieren.

Pitfalls of using sequence databases for heterologous expression studies – a technical review

Abstract: Synthesis of DNA fragments based on gene sequences that are available in public resources has become an efficient and affordable method that has gradually replaced traditional cloning efforts such as PCR cloning from cDNA. However, database entries based on genome sequencing results are prone to errors which can lead to false sequence information and, ultimately, errors in functional characterisation of proteins such as ion channels and transporters in heterologous expression systems. We have identified five common problems that repeatedly appear in public resources: (1) Not every gene has yet been annotated; (2) not all gene annotations are necessarily correct; (3) transcripts may contain automated corrections; (4) there are mismatches between gene, mRNA and protein sequences; and (5) splicing patterns often lack experimental validation. This technical review highlights and provides a strategy to bypass these issues in order to avoid critical mistakes that could impact future studies of any gene/protein of interest in heterologous expression systems.

Association of hydrochlorothiazide treatment compared with alternative diuretics with overall and skin cancer risk: a propensity-matched cohort study

Abstract: Introduction: Hydrochlorothiazide (HCT) has been suggested to induce photosensitivity, thereby increasing the incidence of skin cancers. After a pharmacovigilance alert, HCT was frequently withdrawn or substituted by other diuretics. The aim of this study was to compare the association of exposure to HCT with cancer risk versus alternative diuretics. Methods: A retrospective cohort study was conducted based on data from the AOK PLUS, a large German statutory health insurance fund. Patients with HCT treatment were propensity score matching to patients using non-HCT diuretics. Incidence of cancer of any kind and, specifically, skin cancer was assessed in both groups. Time-to-incident cancer diagnosis was evaluated and compared between the groups. Results: A total of 199 708 patients were included in the final analysis (n = 76 855 in the HCT group; n = 122 853 in the non-HCT-diuretics group). After propensity score matching, 122 554 patients remained in the sample (n = 61 277 for both groups, of which >96% had hypertension, mean age 73 years, 61% female). HCT treatment was associated with a lower incidence of cancer of any kind compared with non-HCT diuretics (incidence rate ratio per 100 patient years 0.84 95% confidence interval: 0.82–0.87). HCT treatment was associated with a small albeit significantly higher incidence rate ratio of skin cancer (1.14 95% confidence interval: 1.06–1.24) with significant variances over time. Although numerically higher, the difference accounts to only 0.05 more skin cancer diagnoses in 100 patient-years. Conclusion: HCT treatment compared with alternative diuretics was associated with a lower all-cancer risk and a numerically small increased skin cancer risk in a large German population. Risk–benefit evaluation should be executed in patients with increased skin cancer risk and treatment with HCT. Furthermore, advice for skin protection is warranted in all patients taking thiazide or thiazide-like diuretics.

Twenty-five Years of Root Remodeling for Root Aneurysm and Tricuspid Aortic Valve

Abstract: Abstract OBJECTIVES The aim of this retrospective study was to assess the long-term results of root remodelling with tricuspid aortic valves and the effects of concomitant cusp repair and annuloplasty. METHODS Between October 1995 and December 2021, 684 patients with root aneurysm and regurgitant tricuspid valves were treated by root remodelling. The mean age was 56.5 [standard deviation (SD): 14] years, and 538 (77.6%) were male. Relevant aortic regurgitation was present in 68.3%. Concomitant procedures were performed in 374 patients. The long-term results were analysed. The mean follow-up of 7.2 (SD: 5.3) years (median 6.6 years); it was 95% complete (4934.4 patient-years). RESULTS Cusp prolapse was repaired in 83%, and an annuloplasty was added in 353 instances (51.6%). Hospital mortality was 2.3%, and survival was 81.7% (SD: 1.2) and 55.7% (SD: 5.8) at 10 and 20 years; age and measurement of effective height were independent predictors for death. Freedom from Aortic insufficiency (AI) II was 90.5 (SD: 1.9) at 10 years and 76.7 (SD: 4.5) at 20 years. Cusp repair of all cusps showed a lower freedom from recurrent AI ≥II at 10 years (P < 0.001). Suture annuloplasty showed a lower freedom from recurrent AI II at 10 years (P = 0.07). Freedom from reoperation was 95.5 (SD: 1.1) and 92.8 (SD: 2.8) at 10 and 20 years. The addition of an annuloplasty showed no difference (P = 0.236). Cusp repair had no effect on valve durability (P = 0.390). CONCLUSIONS Root remodelling leads to good long-term stability. The addition of cusp repair improves the valve stability over time. The addition of suture annuloplasty improves early valve competency; it showed no effect on freedom from reoperation up to 10 years.

Equivalence of Charge Imbalance and External Electric Fields during Free Energy Calculations of Membrane Electroporation

Abstract: Electric fields across lipid membranes play important roles in physiology, medicine, and biotechnology, rationalizing the wide interest in modeling transmembrane potentials in molecular dynamics simulations. Transmembrane potentials have been implemented with external electric fields or by imposing charge imbalance between the two water compartments of a stacked double-membrane system. We compare the two methods in the context of membrane electroporation, which involves a large change of membrane structure and capacitance. We show that, given that Ewald electrostatics are defined with tinfoil boundary conditions, the two methods lead to (i) identical potentials of mean force (PMFs) of pore formation and expansion at various potentials, demonstrating that the two methods impose equivalent driving forces for large-scale transitions at membranes, and (ii) to identical polarization of water within thin water wires or open pores, suggesting that the two methods furthermore impose equivalent local electric fields. Without tinfoil boundary conditions, effects from external fields on pore formation are spuriously suppressed or even removed. Together, our study shows that both methods, external fields and charge imbalance, are well suitable for studying large-scale transitions of lipid membranes that involve changes of membrane capacitance. However, using charge imbalance is technically more challenging for maintaining a constant transmembrane potential since it requires updating of the charge imbalance as the membrane capacitance changes.

Chemosensory cells in the respiratory tract as crucial regulators of innate immune responses

Abstract: During recent years chemosensory cells in extraoral tissues have been established as mediators for the detection and regulation of innate immune processes in response to pathogens. Under physiological conditions, chemosensory cells are present throughout the respiratory epithelium of the upper and lower airways as well as in the main olfactory epithelium. Additionally, they emerge in the alveolar region of the lung upon viral infections. Chemosensory cells in the upper and the lower airways detect signalling molecules from gram-positive and gram-negative bacteria as well as aeroallergens and fungi. Upon stimulation they release multiple molecules, such as the transmitter acetylcholine, the cysteinyl leukotriene E4 and the cytokine interleukin-25, which act as autocrine and paracrine signals and thereby orchestrate the innate immune responses in the respiratory system. Activation of chemosensory cells stimulates various immune cells, e.g. type 2 innate lymphoid cells, modulates mucociliary clearance and induces a protective neurogenic inflammation. This review compiles and discusses recent findings regarding chemosensory cell function in the respiratory tract.

A Photoreceptor‐Based Hydrogel with Red Light‐Responsive Reversible Sol‐Gel Transition as Transient Cellular Matrix

Abstract: Hydrogels with adjustable mechanical properties have been engineered as matrices for mammalian cells and allow the dynamic, mechano-responsive manipulation of cell fate and function. Recent research yields hydrogels, where biological photoreceptors translated optical signals into a reversible and adjustable change in hydrogel mechanics. While their initial application provides important insights into mechanobiology, broader implementation is limited by a small dynamic range of addressable stiffness. Herein, this limitation is overcome by developing a photoreceptor-based hydrogel with reversibly adjustable stiffness from ≈800 Pa to the sol state. The hydrogel is based on star-shaped polyethylene glycol, functionalized with the red/far-red light photoreceptor phytochrome B (PhyB), or phytochrome-interacting factor 6 (PIF6). Upon illumination with red light, PhyB heterodimerizes with PIF6, thus crosslinking the polymers and resulting in gelation. However, upon illumination with far-red light, the proteins dissociate and trigger a complete gel-to-sol transition. The hydrogel's light-responsive mechanical properties are comprehensively characterized and it is applied as a reversible extracellular matrix for the spatiotemporally controlled deposition of mammalian cells within a microfluidic chip. It is anticipated that this technology will open new avenues for the site- and time-specific positioning of cells and will contribute to overcome spatial restrictions.

Non-destructive Materials Characterization by Electromagnetic Techniques

Abstract: In this chapter, electro-magnetic (EM) and micro-magnetic (MM) techniques for applications in non-destructive material characterization (NDMC) are discussed. While EM techniques can be used for all electrically conducting and ferromagnetic materials, MM techniques are applicable only to ferromagnetic materials. There are many commonalities between the EM and MM techniques in terms of the sensors’ primary excitation and reception of secondary magnetic fields. After explaining the basic concepts of conductivity, electromagnetism, and magnetic properties of materials, applications of these for the characterization of microstructuresMicrostructure and stresses are presented. The effects of conductivity and permeabilityBarkhausen noisepermeability of materials on the amplitude and phase of eddy current signals are analyzed for use in NDMC. Furthermore, the physical principles underlying various magnetic hysteresis loop parameters and MM parameters are discussed, followed by their applications in the field of metallurgical engineering and material science. The analogy of the dislocationDislocation movement under stress fields, which determines the mechanical properties, and the domain-wall movement under magnetic fields governing the magnetic properties provide the means for NDMC.

Influence of topography on electrical contact resistance of copper-based materials

Abstract: Abstract The design of an electrical contact is crucial to ensure optimal performance, reliability, and efficiency of connectors. One key aspect is the surface quality of the contacting bodies – among other factors such as material selection, contact geometry, etc. In this work, we evaluated the influence on electrical contact resistance (ECR) of a smooth copper-based surface (brass, bronze, and tin-plated copper) when contacted against surfaces with different degrees of roughness. Furthermore, a carbon nanotube (CNT) coating was proposed with the goal of mitigating the topography-induced influence of the textured counter electrodes. The electrodes and counter electrodes were thoroughly characterized to understand the contacting mechanisms through numerical modeling, – namely, Greenwood-Williamson and Jackson-Green models – as well as using a practical-oriented slope analysis. Load-dependent ECR measurements were carried out to quantify the effect of roughness on contact resistance. When contacting against brass and bronze, a clear correlation between roughness and ECR can be established, with higher roughness equating to lower ECR. In tin-plated copper, on the other hand, this hierarchy is not as well defined due to the ease with which the tin plating deforms, thus enabling the penetration of outstanding asperities and consequently establishing a better electrical contact. CNT-coated counter electrodes showed promising results, partially confirming the hypothesis proposed. However, unforeseen topography-related interactions with the CNT coating produced exceptions in the ECR measurements. Nonetheless, for most cases studied the coating did mitigate the influence of roughness.

A novel Rift Valley fever vaccine

Abstract: The past decade has seen advances in knowledge of classic and next-generation vaccine principles, including mRNA-based delivery and vector vaccines. Modified replication-incompetent chimpanzee adenovirus (ChAdOx1) vectors expressing different antigens for diseases such as Ebola virus disease, influenza, malaria, or Middle East respiratory syndrome have entered clinical trials1Folegatti PM Jenkin D Morris S et al.Vaccines based on the replication-deficient simian adenoviral vector ChAdOx1: standardized template with key considerations for a risk/benefit assessment.Vaccine. 2022; 40: 5248-5262Crossref PubMed Scopus (5) Google Scholar and, in response to the COVID-19 pandemic, ChAdOx1 rapidly advanced as vector for one of the most widely used COVID-19 vaccines worldwide.2Voysey M Clemens SAC Madhi SA et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2021; 397: 99-111Summary Full Text Full Text PDF PubMed Scopus (2819) Google Scholar Both mRNA vaccines and vector vaccines towards SARS-CoV-2 were well tolerated, strongly immunogenic, and achieved remarkable efficacy and effectiveness in real-world studies.2Voysey M Clemens SAC Madhi SA et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2021; 397: 99-111Summary Full Text Full Text PDF PubMed Scopus (2819) Google Scholar, 3Baden LR El Sahly HM Essink B et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (5255) Google Scholar, 4Polack FP Thomas SJ Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (7786) Google Scholar ChAdOx1 vectors therefore provide a promising basis to generate immunological protection against other infectious diseases. In this issue of The Lancet Infectious Diseases, Daniel Jenkin and colleagues5Jenkin D Wright D Folegatti PM et al.Safety and immunogenicity of a ChAdOx1 vaccine against Rift Valley fever in UK adults: an open-label, non-randomised, first-in-human phase 1 clinical trial.Lancet Infect Dis. 2023; (published online April 12.)https://doi.org/10.1016/S1473-3099(23)00068-3Google Scholar report results of a phase 1 study of a new ChAdOx1 vector vaccine against Rift Valley fever (RVF), a mosquito-borne viral zoonotic disease. Safety and immunogenicity of a single dose of the vaccine were characterised in a first-in-human, open-label trial of 15 healthy volunteers from the UK aged 18–55 years. The vaccine was tested in three doses, of which the two highest showed more pronounced immunogenicity. It induced both antibodies and T cells, which persisted during the 3-month follow-up. The vaccine was well tolerated with mild to moderate adverse events, such as fever and fatigue, more frequently occurring in the higher dose groups. Despite a small sample size and restriction to UK adult study participants only, the data provide a promising example of another vaccine against a high-burden disease in humans. The favourable safety and immunogenicity data from this vaccine candidate in UK adults clearly support advancement of this vaccine to phase 2 clinical evaluation in RVF-endemic countries. The development of an effective human vaccine against RVF that elicits a long-term immune response across all age groups at risk of exposure is of enormous clinical importance. Other than a minor role of mosquitoes in transmission, infection of humans occurs after direct contact with infected animal tissues.6Anywaine Z Lule SA Hansen C Warimwe G Elliott A Clinical manifestations of Rift Valley fever in humans: systematic review and meta-analysis.PLoS Negl Trop Dis. 2022; 16e0010233Crossref PubMed Scopus (5) Google Scholar A vector-based vaccine for livestock has already been developed to limit transmission. Although most infected individuals develop a self-limiting, febrile illness, a small proportion will experience more severe symptoms, including haemorrhagic diatheses, meningoencephalitis, and ocular pathology. Furthermore, the risk of miscarriage is increased in people who are pregnant and infected with RVF virus.6Anywaine Z Lule SA Hansen C Warimwe G Elliott A Clinical manifestations of Rift Valley fever in humans: systematic review and meta-analysis.PLoS Negl Trop Dis. 2022; 16e0010233Crossref PubMed Scopus (5) Google Scholar Advantages of ChAdOx1-based vector vaccines are the potential for relatively fast production and for storage, transport, and handling in refrigerated conditions. These advantages will enable wide access to the vaccine for the target population that includes children, adolescents, and adults, including people who are pregnant. We are convinced that evaluation of the RVF vaccine in phase 2/3 trials will benefit from the knowledge gained by the comprehensive data on safety, immunogenicity, and effectiveness of the ChAdOx1-COVID-19 vaccine, including both promising and concerning aspects encountered during clinical studies and mass application in a real-world setting. Although the study participants in the trial of the RVF vaccine were White and had not been vaccinated with a ChAdOx1 vaccine before, the ChAdOx1-COVID-19 vaccine was already used in 180 countries, including regions endemic for RVF. This widespread exposure to the ChAdOx1-COVID-19 vaccine could reduce immunogenicity of other vector vaccines subsequently administered. There is a clear need for further study on immunogenicity of the vaccine in the endemic target population, including children and people who are pregnant, as little or no data are available on the ChAdOx1-COVID-19 vaccine for these groups. Furthermore, although children were less likely to be exposed to the vector, natural immunity towards adenoviruses is generally more pronounced in children than in adults,7Sester M Sester U Alarcon Salvador S et al.Age-related decrease in adenovirus-specific T cell responses.J Infect Dis. 2002; 185: 1379-1387Crossref PubMed Scopus (52) Google Scholar which might disproportionally decrease immunogenicity towards a vaccine with an adenovirus vector basis. Whether one dose of the RVF vaccine is sufficient to confer protection is unclear. Individuals on a single-dose COVID-19 vaccine regimen were more likely to have breakthrough infections.8Self WH Tenforde MW Rhoads JP et al.Comparative effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) vaccines in preventing COVID-19 hospitalizations among adults without immunocompromising conditions—United States, March-August 2021.MMWR Morb Mortal Wkly Rep. 2021; 70: 1337-1343Crossref PubMed Google Scholar Further study is warranted to assess whether RVF infections in recipients of a single-dose vaccine will remain asymptomatic and act as natural boosting after vaccine priming or whether a single dose of the RVF vaccine will entail higher rates of symptomatic breakthrough infections. If a second dose were required, the lower immunogenicity observed after two homologous doses of the ChAdOx1-COVID-19 vaccine might be balanced against heterologous regimens of vector priming and mRNA boosting or protein boosting, which not only led to higher antibody levels but also to more pronounced T-cell responses.9Schmidt T Klemis V Schub D et al.Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination.Nat Med. 2021; 27: 1530-1535Crossref PubMed Scopus (196) Google Scholar Long-term studies of the RVF vaccine will require monitoring of rare adverse events, such as life-threatening cerebral venous thrombosis and thrombocytopenia, which mainly occurred after ChAdOx1-COVID-19 vaccination in young women.10Greinacher A Thiele T Warkentin TE Weisser K Kyrle PA Eichinger S Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.N Engl J Med. 2021; 384: 2092-2101Crossref PubMed Scopus (1348) Google Scholar Thus, although we eagerly await further data on immunogenicity and efficacy of the RVF vaccine, the successes and the disadvantages of the ChAdOx1-COVID-19 vaccine could already provide insight into key questions and potential answers that could similarly apply to other vector-based vaccines. MS is an Investigator for Biotest; receives consulting fees from Biotest, Merck Sharp & Dohme, and Takeda; receives honoraria from Biotest, Merck Sharp & Dohme, Takeda, Novartis, and Qiagen; receives support for attending meetings and travel from Biotest and Takeda; is a member of Data Safety Monitoring Boards or Advisory Boards for Biotest, Takeda, and Moderna; and is a member of the Tuberculosis Network European Trials group Steering Committee. SB declares no competing interests. Safety and immunogenicity of a ChAdOx1 vaccine against Rift Valley fever in UK adults: an open-label, non-randomised, first-in-human phase 1 clinical trialChAdOx1 RVF was safe, well tolerated, and immunogenic when administered as a single dose in this study population. The data support further clinical development of ChAdOx1 RVF for human use. Full-Text PDF Open Access

Non-destructive Materials Characterization using Ionizing Radiation

Abstract: This chapter discusses the physical principles and the applications of non-destructive materials characterization (NDMC) techniques using X-rays, neutronsNeutrons, electrons, and positrons. Various means of generation and detection of X-rays are presented followed by the basics of their interaction with materials. These interactions lead to attenuation and diffraction, which are elucidated by examples from different metallurgical and material science applications of NDMC. The basics of X-ray diffraction and their applications for the measurement of elastic stresses at different length scales and of textures are discussed as well. The specific differences of the interaction of neutronsNeutrons with materials as compared to X-rays in radiography and scattering studies are worked out. Applications of electron and positron annihilation for NDMC are also discussed.

Fatter Is Better: Boosting the Vascularization of Adipose Tissue Grafts

Abstract: Adipose tissue resorption after fat grafting is a major drawback in plastic and reconstructive surgery, which is primarily caused by the insufficient blood perfusion of the grafts in the initial phase after transplantation. To overcome this problem, several promising strategies to boost the vascularization and, thus, increase survival rates of fat grafts have been developed in preclinical studies in recent years. These include the angiogenic stimulation of the grafts by growth factors and botulinum neurotoxin A, biologically active gels, and cellular enrichment, as well as the physical and pharmacological stimulation of the transplantation site. To transfer these approaches into future clinical practice, it will be necessary to establish standardized procedures for their safe application in humans. If this succeeds, the surgical outcomes of fat grafting may be markedly improved, resulting in a significant reduction of the physical and psychological stress for the patients. The present review provides for the first time a complete overview of strategies for the acceleration and improvement of fat graft vascularization that have been established in preclinical models. Since a sufficient vascularization is a major prerequisite for the long-term survival of fat grafts, these strategies may crucially contribute to an improved outcome of fat transplantation in future clinical practice.

Releasing survey microdata with exact cluster locations and additional privacy safeguards

Abstract: Abstract Household survey programs around the world publish fine-granular georeferenced microdata to support research on the interdependence of human livelihoods and their surrounding environment. To safeguard the respondents’ privacy, micro-level survey data is usually (pseudo)-anonymized through deletion or perturbation procedures such as obfuscating the true location of data collection. This, however, poses a challenge to emerging approaches that augment survey data with auxiliary information on a local level. Here, we propose an alternative microdata dissemination strategy that leverages the utility of the original microdata with additional privacy safeguards through synthetically generated data using generative models. We back our proposal with experiments using data from the 2011 Costa Rican census and satellite-derived auxiliary information. Our strategy reduces the respondents’ re-identification risk for any number of disclosed attributes by 60–80% even under re-identification attempts.

Radiation and Dose-densification of R-CHOP in Primary Mediastinal B-cell Lymphoma: Subgroup Analysis of the UNFOLDER Trial

Abstract: UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.

Total Synthesis of Thiamyxins A–C and Thiamyxin E, a Potent Class of RNA‐Virus‐Inhibiting (Cyclo)depsipeptides

Abstract: We present the first total synthesis of the thiamyxins A-C and the now fully characterized thiamyxin E, an interesting class of thiazole- and thiazoline-rich depsipeptides with diverse antiviral activity. The synthesis features a parallel closing of two methyl thiazoline units, with low epimerization of the very labile adjacent stereocenter. It also includes the three-step synthesis of an uncommon hydroxy acid and the oxidation-free elimination of a phenylselenide to form a dehydroalanine moiety. The exploitation of the acid labile stereocenter at the isoleucine moiety and the reopening of the macrolactones gave access to the four thiamyxins with good yields and diastereomeric purities from a single precursor. The modular total synthesis allows further testing of the biological activity and gives opportunities to explore the pharmacophore and antiviral target via derivatization.

Ultrasonic Non-destructive Materials Characterization

Abstract: The propagation of ultrasonic waves through materials is essentially governed by its elastic and anelastic properties. Following the basics of interatomic forces and elasticity, ultrasonic velocities in single crystals and polycrystalline materials are discussed in chapter 1 in detail, providing means for materials characterization using ultrasonic velocity measurements. The third-order elastic constants in polycrystalline materials describe the acoustoelastic constants which form the basis for the evaluation of elastic stresses in materials. Stresses lead to anisotropic velocities and so do textures. It is discussed how these can be separated. The anisotropy of the constituents of the microstructure of a material leads to ultrasonic scattering and therefore to attenuation of the propagating waves, whereas the anelasticity in lattice structure leads to internal friction. Both effects are discussed with various examples. Fatigue and creep manifest themselves in the parameters describing ultrasonic propagation and hence can be exploited for non-destructive materials characterization (NDMCNDMC). Thus, in chapter 1, we emphasize the principles forming the basis for NDMC NDMCTexture measurement using ultrasonics and demonstrate their applications through suitable examples.

Automata-Based Software Model Checking of Hyperproperties

Abstract: We develop model checking algorithms for Temporal Stream Logic (TSL) and Hyper Temporal Stream Logic (HyperTSL) modulo theories. TSL extends Linear Temporal Logic (LTL) with memory cells, functions and predicates, making it a convenient and expressive logic to reason over software and other systems with infinite data domains. HyperTSL further extends TSL to the specification of hyperproperties – properties that relate multiple system executions. As such, HyperTSL can express information flow policies like noninterference in software systems. We augment HyperTSL with theories, resulting in HyperTSL(T), and build on methods from LTL software verification to obtain model checking algorithms for TSL and HyperTSL(T). This results in a sound but necessarily incomplete algorithm for specifications contained in the $$\forall ^*\exists ^*$$ fragment of HyperTSL(T). Our approach constitutes the first software model checking algorithm for temporal hyperproperties with quantifier alternations that does not rely on a finite-state abstraction.

The world of deviance in the classroom: Psychological experiments on schoolchildren in Weimar Germany

Abstract: The article uses three case studies from the 1920s to explore how psychologists and elementary school teachers employed psychological techniques to gain knowledge about elementary school children and their milieu. It begins by describing the role of the elementary school and the elementary school teacher in the Weimar Republic. It then discusses the so-called "observation sheets" that were used in elementary schools in the 1920s to gain insights into the mental and moral characteristics of pupils. Third, it examines psychological experiments undertaken in elementary school classrooms based on the exemplar case of a single teacher/experimenter, before concluding with a comparison of the two practices. I argue that psychology gained in standing through this history, becoming recognized as a foundational science in the context of education. Teachers used the professionalization of observation techniques in school to enhance their socio-epistemic status.

Three-dimensional imaging of microstructural evolution in SEM-based nano-CT

Abstract: Scanning electron microscopy (SEM) is a powerful and versatile technique for materials characterization and present in many laboratories. The integration of an X-ray target holder and detector allows expanding the modalities of SEM by X-ray imaging. These little hardware adaptations enable radiography or X-ray computed tomography (CT) to gain three-dimensional (3D) information about a sample to be investigated. Since SEM-based CT is a non-destructive technique, the method can also image time-dependent changes in microstructure. Presented is the ability of SEM-based nano-CT to image the microstructural evolution of an aluminum-germanium (AlGe32) alloy as a result of annealing. First, the non-destructive CT method is used for an overview scan to identify a hidden region of interest (ROI) in the sample volume at low resolution. The following FIB target preparation reveals the microstructure, which is stepwise annealed and investigated with SEM-based nano-CT at high resolution afterwards. The resulting reconstructed volumes gained from the laboratory-based system are visualized in 3D and show the morphology changes of microstructure. Quantitative analysis reveals grain coarsening and the formation of precipitations in the size of 300–1000 nm. These time-dependent processes are additionally correlated with hardness measurements of the Al alloy.