T Cell Receptor (TCR) Antagonism without a Negative Signal: Evidence from T Cell Hybridomas Expressing Two Independent TCRs

Antagonist peptides inhibit T cell responses by an unknown mechanism. By coexpressing two independent T cell receptors (TCRs) on a single T cell hybridoma, we addressed the question of whether antagonist ligands induce a dominant-negative signal that inhibits the function of a second, independent TCR. The two receptors, Vα2Vβ5 and Vα2Vβ10, restricted by H-2Kb and specific for the octameric peptides SIINFEKL and SSIEFARL, respectively, were coexpressed on the same cell. Agonist stimulation demonstrated that the two receptors behaved independently with regard to antigen-induced TCR downregulation and intracellular biochemical signaling. The exposure of one TCR (Vα2Vβ5) to antagonist peptides could not inhibit a second independent TCR (Vα2Vβ10) from responding to its antigen. Thus, our data clearly demonstrate that these antagonist ligands do not generate a dominant-negative signal which affects the responsiveness of the entire cell. In addition, a kinetic analysis showed that even 12 h after engagement with their cognate antigen and 10 h after reaching a steady-state of TCR internalization, T cells were fully inhibited by the addition of antagonist peptides. The window of susceptibility to antagonist ligands correlated exactly with the time required for the responding T cells to commit to interleukin 2 production. The data support a model where antagonist ligands can competitively inhibit antigenic peptides from productively engaging the TCR. This competitive inhibition is effective during the entire commitment period, where sustained TCR engagement is essential for full T cell activation

Perioperative factor concentrate therapy

Transfusion of allogeneic plasma has been a life-saving measure for decades in patients with severe trauma or suffering from major surgical blood loss. The safety of allogeneic blood components has improved in terms of pathogen transmission, but haemostatic efficacy of plasma is hindered by the large volume and time required for thawing and infusion. Several plasma-derived and recombinant factor concentrates are clinically available and indicated for targeted replacement of missing coagulation elements in hereditary disorders of thrombosis and haemostasis. When used appropriately, factor concentrate therapy can rapidly restore deficient factor(s) without causing volume overload. The haemostatic defect in perioperative patients is often multifactorial, and therefore careful clinical judgement and timely coagulation testing must be exercised before the administration of factor concentrates. In this review, the rationale for including factor concentrates in perioperative haemostatic management will be discussed in conjunction with the limitations of plasma transfusio

Haemodilution-induced profibrinolytic state is mitigated by fresh-frozen plasma: implications for early haemostatic intervention in massive haemorrhage

Background Fibrinolysis contributes to coagulopathy after major trauma and surgery. We hypothesized that progressive haemodilution is responsible, at least in part, for increased fibrinolytic tendency of blood clot. Methods The study was performed in two parts. First, whole blood (WB) samples collected from six healthy, consented volunteers were diluted in vitro with either saline or fresh-frozen plasma (FFP) to 40% and 15% of baseline. We quantified factor levels related to coagulation and fibrinolysis, and measured endogenous thrombin generation in undiluted control plasma samples and in samples diluted with saline or FFP. Additionally, thromboelastometry was used to assess susceptibility to fibrinolysis after adding tissue plasminogen activator in undiluted WB samples and in samples diluted with saline before and after substitution of fibrinogen or FFP. Secondly, as a model of in vivo haemodilution, we evaluated the same parameters before and after operation in nine consented patients undergoing off-pump coronary artery bypass surgery. Results The dilution with saline caused dose-dependent decreases in plasma levels of coagulation and antifibrinolytic factors, and in thrombin generation. In FFP-supplemented samples, factor levels and thrombin generation were maintained within normal ranges. Fibrinolytic tendency was significantly higher after haemodilution with saline independent of fibrinogen substitution compared with FFP. Similarly, increased tendency for fibrinolysis was also observed in the in vivo haemodilution. Conclusions We demonstrated in vitro and in vivo that progressive haemodilution decreases endogenous antifibrinolytic proteins including α2-antiplasmin and thrombin-activatable fibrinolysis inhibitor, resulting in increased fibrinolytic tendency. Therefore, early fluid replacement therapy with FFP might be advantageous after massive haemorrhag

Validity and reliability of the 2-minute walk test in individuals with spinal cord injury

STUDY DESIGN Multicentre-observational study. OBJECTIVES The 6-minute walk test (6mWT) is an established assessment of walking function in individuals with spinal cord injury (SCI). However, walking 6 min can be demanding for severely impaired individuals. The 2-minute walk test (2mWT) could be an appropriate alternative that has already been validated in other neurological disorders. The aim of this study was to assess construct validity and test-rest reliability of the 2mWT in individuals with SCI. In addition, the influence of walking performance on sensitivity to change of the 2mWT was assessed. SETTING Swiss Paraplegic Center Nottwil, Switzerland; Balgrist University Hospital, Zürich, Switzerland. METHODS Fifty individuals (aged 18-79) with SCI (neurological level of injury: C1-L3, AIS: A-D) were assessed on two test days separated by 1 to 7 days. The first assessment consisted of a 2mWT familiarization, followed by a 2mWT and 10-meter walk test (10MWT) (including the Walking Index for Spinal Cord Injury (WISCI II)) in randomized order. The second assessment consisted of 2mWT and 6mWT in randomized order. Tests were separated by at least 30 min of rest. RESULTS The interclass correlation coefficient between the 2mWT assessed on the first and second test day was excellent (r = 0.980, p < 0.001). The 2mWT correlated very strongly with the 6mWT (r = 0.992, p < 0.001) and the 10MWT (r = 0.964, p < 0.001), and moderately with the WISCI II (r = 0.571, p < 0.001). Sensitivity to change was slightly affected by walking performance. CONCLUSION The 2mWT is a valid and reliable alternative to the 6mWT to measure walking function in individuals with SCI. TRIAL REGISTRATION NCT04555759

New insights into early bronze age damascene technique north of the alps

Damascening, defined in this context as the inlay of one metal into a different metal base, is a rare decorative technique in the Early Bronze Age, known only from seven bronze artefacts found north of the Alps. This paper reports on the first thorough scientific examination of one such find, the axe from Thun-Renzenbühl grave no. 1. This interdisciplinary project involving several institutions in Germany and Switzerland investigated the axe by means of neutron radiographic imaging and X-ray microprobe methods, supported by microscopic examination. The result is an attempt to reconstruct the fabrication and decoration process and to reconsider the enigmatic question of the origins of the damascene technique north of the Alp

The surface science of quasicrystals

The surfaces of quasicrystals have been extensively studied since about 1990. In this paper we review work on the structure and morphology of clean surfaces, and their electronic and phonon structure. We also describe progress in adsorption and epitaxy studies. The paper is illustrated throughout with examples from the literature. We offer some reflections on the wider impact of this body of work and anticipate areas for future development. (Some figures in this article are in colour only in the electronic version

DSCIM-Coastal v1.1: an open-source modeling platform for global impacts of sea level rise

Sea level rise (SLR) may impose substantial economic costs to coastal communities worldwide, but characterizing its global impact remains challenging because SLR costs depend heavily on natural characteristics and human investments at each location – including topography, the spatial distribution of assets, and local adaptation decisions. To date, several impact models have been developed to estimate the global costs of SLR. Yet, the limited availability of open-source and modular platforms that easily ingest up-to-date socioeconomic and physical data sources restricts the ability of existing systems to incorporate new insights transparently. In this paper, we present a modular, open-source platform designed to address this need, providing end-to-end transparency from global input data to a scalable least-cost optimization framework that estimates adaptation and net SLR costs for nearly 10 000 global coastline segments and administrative regions. Our approach accounts both for uncertainty in the magnitude of global mean sea level (g.m.s.l.) rise and spatial variability in local relative sea level rise. Using this platform, we evaluate costs across 230 possible socioeconomic and SLR trajectories in the 21st century. According to the latest Intergovernmental Panel on Climate Change Assessment Report (AR6), g.m.s.l. is likely to rise during the 21st century by 0.40–0.69 m if late-century warming reaches 2 ∘C and by 0.58–0.91 m with 4 ∘C of warming (Fox-Kemper et al., 2021). With no forward-looking adaptation, we estimate that annual costs of sea level rise associated with a 2 ∘C scenario will likely fall between USD 1.2 and 4.0 trillion (0.1 % and 1.2 % of GDP, respectively) by 2100, depending on socioeconomic and sea level rise trajectories. Cost-effective, proactive adaptation would provide substantial benefits, lowering these values to between USD 110 and USD 530 billion (0.02 and 0.06 %) under an optimal adaptation scenario. For the likely SLR trajectories associated with 4 ∘C warming, these costs range from USD 3.1 to 6.9 trillion (0.3 % and 2.0 %) with no forward-looking adaptation and USD 200 billion to USD 750 billion (0.04 % to 0.09 %) under optimal adaptation. The Intergovernmental Panel on Climate Change (IPCC) notes that deeply uncertain physical processes like marine ice cliff instability could drive substantially higher global sea level rise, potentially approaching 2.0 m by 2100 in very high emission scenarios. Accordingly, we also model the impacts of 1.5 and 2.0 m g.m.s.l. rises by 2100; the associated annual cost estimates range from USD 11.2 to 30.6 trillion (1.2 % and 7.6 %) under no forward-looking adaptation and USD 420 billion to 1.5 trillion (0.08 % to 0.20 %) under optimal adaptation. Our modeling platform used to generate these estimates is publicly available in an effort to spur research collaboration and support decision-making, with segment-level physical and socioeconomic input characteristics provided at https://doi.org/10.5281/zenodo.7693868 (Bolliger et al., 2023a) and model results at https://doi.org/10.5281/zenodo.7693869 (Bolliger et al., 2023b).</p

situ assessment of microbial sulfate reduction in a petroleum-contaminated aquifer using push-pull tests and stable sulfur isotope analyses

Abstract Anaerobic microbial activities such as sulfate reduction are important for the degradation of Ž . petroleum hydrocarbons PHC in contaminated aquifers. The objective of this study was to evaluate the feasibility of single-well push-pull tests in combination with stable sulfur isotope analyses for the in situ quantification of microbial sulfate reduction. A series of push-pull tests Ž was performed in an existing monitoring well of a PHC-contaminated aquifer in Studen Switzer-. land . Sulfate transport behavior was evaluated in a first test. In three subsequent tests, we injected Ž . Ž y . anoxic test solutions up to 1000 l , which contained 0.5 mM bromide Br as conservative tracer Ž 2y . and 1 mM sulfate SO as reactant. Ž . PII: S 0 1 6 9 -7 7 2 2 0 1 0 0 1 2 8 -0 Schroth et al.r Journal of Contaminant Hydrology 51 2001 179-195 180 analyses proved useful for the in situ quantification of microbial sulfate reduction in a PHC-contaminated aquifer.

Introduction: animal law in a nutshell

The introduction explains key concepts and methods. It defines global animal law as the sum of legal rules and principles governing the interactions between humans and other animals, on a domestic, local, regional, and international level. Global animal law reacts to the mismatch between almost exclusively national animal-related legislation on the one hand, and the global dimension of the animal issue on the other hand. The merely national regulation of animal welfare within the states’ boundaries runs aloof in the face of globalisation. This gives rise to an animal welfare gap. Moreover, animal use creates global problems ranging from climate and soil degradation over antimicrobial resistance to food insecurity. This requires a global law response. The introduction also gives a brief overview over the book and its main findings