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

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

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

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

Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage.

The hollow cavities of coordination cages can provide an environment for enzyme-like catalytic reactions of small-molecule guests. Here, we report a new example (catalysis of the Kemp elimination reaction of benzisoxazole with hydroxide to form 2-cyanophenolate) in the cavity of a water-soluble M8L12 coordination cage, with two features of particular interest. First, the rate enhancement is among the largest observed to date: at pD 8.5, the value of kcat/kuncat is 2 × 10(5), due to the accumulation of a high concentration of partially desolvated hydroxide ions around the bound guest arising from ion-pairing with the 16+ cage. Second, the catalysis is based on two orthogonal interactions: (1) hydrophobic binding of benzisoxazole in the cavity and (2) polar binding of hydroxide ions to sites on the cage surface, both of which were established by competition experiments

In Vivo Evaluation of the Biocompatibility of Surface Modified Hemodialysis Polysulfone Hollow Fibers in Rat

Polysulfone (Psf) hollow fiber membranes (HFMs) have been widely used in blood purification but their biocompatibility remains a concern. To enhance their biocompatibility, Psf/TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate) composite HFMs and 2-methacryloyloxyethyl phosphorylcholine (MPC) coated Psf HFMs have been prepared. They have been evaluated for in vivo biocompatibility and graft acceptance and compared with sham and commercial membranes by intra-peritoneal implantation in rats at day 7 and 21. Normal body weights, tissue formation and angiogenesis indicate acceptance of implants by the animals. Hematological observations show presence of post-surgical stress which subsides over time. Serum biochemistry results reveal normal organ function and elevated liver ALP levels at day 21. Histological studies exhibit fibroblast recruitment cells, angiogenesis and collagen deposition at the implant surface indicating new tissue formation. Immuno-histochemistry studies show non-activation of MHC molecules signifying biocompatibilty. Additionally, Psf/TPGS exhibit most favorable tissue response as compared with other HFMs making them the material of choice for HFM preparation for hemodialysis applications

The Influence of Different Stresses on Glomalin Levels in an Arbuscular Mycorrhizal Fungus—Salinity Increases Glomalin Content

Glomalin is a glycoprotein produced by arbuscular mycorrhizal (AM) fungi, and the soil fraction containing glomalin is correlated with soil aggregation. Thus, factors potentially influencing glomalin production could be of relevance for this ecosystem process and for understanding AM fungal physiology. Previous work indicated that glomalin production in AM fungi may be a stress response, or related to suboptimal mycelium growth. We show here that environmental stress can enhance glomalin production in the mycelium of the AM fungus Glomus intraradices. We applied NaCl and glycerol in different intensities to the medium in which the fungus was grown in vitro, causing salinity stress and osmotic stress, respectively. As a third stress type, we simulated grazing on the extraradical hyphae of the fungus by mechanically injuring the mycelium by clipping. NaCl caused a strong increase, while the clipping treatment led to a marginally significant increase in glomalin production. Even though salinity stress includes osmotic stress, we found substantially different responses in glomalin production due to the NaCl and the glycerol treatment, as glycerol addition did not cause any response. Thus, our results indicate that glomalin is involved in inducible stress responses in AM fungi for salinity, and possibly grazing stress

Mapping the internal recognition surface of an octanuclear coordination cage using guest libraries

Size and shape criteria for guest binding inside the cavity of an octanuclear cubic coordination cage in water have been established using a new fluorescence displacement assay to quantify guest binding. For aliphatic cyclic ketones of increasing size (from C5 to C11), there is a linear relationship between ΔG for guest binding and the guest’s surface area: the change in ΔG for binding is 0.3 kJ mol–1 Å–2, corresponding to 5 kJ mol–1 for each additional CH2 group in the guest, in good agreement with expectations based on hydrophobic desolvation. The highest association constant is K = 1.2 × 106 M–1 for cycloundecanone, whose volume is approximately 50% of the cavity volume; for larger C12 and C13 cyclic ketones, the association constant progressively decreases as the guests become too large. For a series of C10 aliphatic ketones differing in shape but not size, ΔG for guest binding showed no correlation with surface area. These guests are close to the volume limit of the cavity (cf. Rebek’s 55% rule), so the association constant is sensitive to shape complementarity, with small changes in guest structure resulting in large changes in binding affinity. The most flexible members of this series (linear aliphatic ketones) did not bind, whereas the more preorganized cyclic ketones all have association constants of 104–105 M–1. A crystal structure of the cage·cycloundecanone complex shows that the guest carbonyl oxygen is directed into a binding pocket defined by a convergent set of CH groups, which act as weak hydrogen-bond donors, and also shows close contacts between the exterior surface of the disc-shaped guest and the interior surface of the pseudospherical cage cavity despite the slight mismatch in shape

Linking human impacts to community processes in terrestrial and freshwater ecosystems.

Human impacts such as habitat loss, climate change and biological invasions are radically altering biodiversity, with greater effects projected into the future. Evidence suggests human impacts may differ substantially between terrestrial and freshwater ecosystems, but the reasons for these differences are poorly understood. We propose an integrative approach to explain these differences by linking impacts to four fundamental processes that structure communities: dispersal, speciation, species-level selection and ecological drift. Our goal is to provide process-based insights into why human impacts, and responses to impacts, may differ across ecosystem types using a mechanistic, eco-evolutionary comparative framework. To enable these insights, we review and synthesise (i) how the four processes influence diversity and dynamics in terrestrial versus freshwater communities, specifically whether the relative importance of each process differs among ecosystems, and (ii) the pathways by which human impacts can produce divergent responses across ecosystems, due to differences in the strength of processes among ecosystems we identify. Finally, we highlight research gaps and next steps, and discuss how this approach can provide new insights for conservation. By focusing on the processes that shape diversity in communities, we aim to mechanistically link human impacts to ongoing and future changes in ecosystems