Adiabatic Evolution of Low-Temperature Many-Body Systems.

We consider finite-range, many-body fermionic lattice models and we study the evolution of their thermal equilibrium state after introducing a weak and slowly varying time-dependent perturbation. Under suitable assumptions on the external driving, we derive a representation for the average of the evolution of local observables via a convergent expansion in the perturbation, for small enough temperatures. Convergence holds for a range of parameters that is uniform in the size of the system. Under a spectral gap assumption on the unperturbed Hamiltonian, convergence is also uniform in temperature. As an application, our expansion allows us to prove closeness of the time-evolved state to the instantaneous Gibbs state of the perturbed system, in the sense of expectation of local observables, at zero and at small temperatures. As a corollary, we also establish the validity of linear response. Our strategy is based on a rigorous version of the Wick rotation, which allows us to represent the Duhamel expansion for the real-time dynamics in terms of Euclidean correlation functions, for which precise decay estimates are proved using fermionic cluster expansion.

Cold Atmospheric Plasma Improves the Colonization of Titanium with Primary Human Osteoblasts: An In Vitro Study.

Several studies have shown that cold atmospheric plasma (CAP) treatment can favourably modify titanium surfaces to promote osteoblast colonization. The aim of this study was to investigate the initial attachment of primary human osteoblasts to plasma-treated titanium. Micro-structured titanium discs were treated with cold atmospheric plasma followed by the application of primary human osteoblasts. The microwave plasma source used in this study uses helium as a carrier gas and was developed at the Leibniz Institute for Surface Modification in Leipzig, Germany. Primary human osteoblasts were analyzed by fluorescence and cell biological tests (alkaline phosphatase activity and cell proliferation using WST-1 assay). The tests were performed after 4, 12, and 24 h and showed statistically significant increased levels of cell activity after plasma treatment. The results of this study indicate that plasma treatment improves the initial attachment of primary human osteoblasts to titanium. For the first time, the positive effect of cold atmospheric plasma treatment of micro-structured titanium on the initial colonization with primary human osteoblasts has been demonstrated. Overall, this study demonstrates the excellent biocompatibility of micro-structured titanium. The results of this study support efforts to use cold atmospheric plasmas in implantology, both for preimplantation conditioning and for regeneration of lost attachment due to peri-implantitis.

Lewis-Base-Catalyzed N-Allylation of Silyl Carbamate Latent Pronucleophiles with Allylic Fluorides.

Silyl carbamates, latent pronucleophile surrogates of carbamates, undergo allylation using allylic fluorides in the presence of common Lewis base catalysts. The reactions are rendered enantioselective in the presence of chiral Lewis base catalysts and produce suitably protected derivatives of enantioenriched chiral ß-amino acids. The design of the latent pronucleophile featuring both a silyl group and an electron-deficient carbamate is instrumental in lowering the nucleophilicity of nitrogen and enabling enantioselective allylation in the presence of chiral cinchona alkaloid-based catalysts.

Ecosystem consequences of invertebrate decline.

Human activities cause substantial changes in biodiversity.1,2 Despite ongoing concern about the implications of invertebrate decline,3,4,5,6,7 few empirical studies have examined the ecosystem consequences of invertebrate biomass loss. Here, we test the responses of six ecosystem services informed by 30 above- and belowground ecosystem variables to three levels of aboveground (i.e., vegetation associated) invertebrate community biomass (100%, 36%, and 0% of ambient biomass) in experimental grassland mesocosms in a controlled Ecotron facility. In line with recent reports on invertebrate biomass loss over the last decade, our 36% biomass treatment also represented a decrease in invertebrate abundance (-70%) and richness (-44%). Moreover, we simulated the pronounced change in invertebrate biomass and turnover in community composition across the season. We found that the loss of invertebrate biomass decreases ecosystem multifunctionality, including two critical ecosystem services, aboveground pest control and belowground decomposition, while harvested plant biomass increases, likely because less energy was channeled up the food chain. Moreover, communities and ecosystem functions become decoupled with a lower biomass of invertebrates. Our study shows that invertebrate loss threatens the integrity of grasslands by decoupling ecosystem processes and decreasing ecosystem-service supply.

Responses of rhizosphere fungi to the root economics space in grassland monocultures of different age.

Recent studies on root traits have shown that there are two axes explaining trait variation belowground: the collaboration axis with mycorrhizal partners and the conservation ('fast - slow') axis. However, it is yet unknown whether these trait axes affect the assembly of soilborne fungi. We expect saprotrophic fungi to link to the conservation axis of root traits, whereas pathogenic and arbuscular mycorrhizal fungi link to the collaboration axis, but in opposite directions, as arbuscular mycorrhizal fungi might provide pathogen protection. To test these hypotheses, we sequenced rhizosphere fungal communities and measured root traits in monocultures of 25 grassland plant species, differing in age. Within the fungal guilds, we evaluated fungal species richness, relative abundance and community composition. Contrary to our hypotheses, fungal diversity and relative abundance were not strongly related to the root trait axes. However, saprotrophic fungal community composition was affected by the conservation gradient and pathogenic community composition by the collaboration gradient. The rhizosphere AMF community composition did not change along the collaboration gradient, even though the root trait axis was in line with the root mycorrhizal colonization rate. Overall, our results indicate that in the long term, the root trait axes are linked with fungal community composition.

Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silyl Enol Ethers with Allylic Fluorides.

Lewis base catalyzed allylations of C-centered nucleophiles have been largely limited to the niche substrates with acidic C-H substituted for C-F bonds at the stabilized carbanionic carbon. Herein we report that the concept of latent pronucleophiles serves to overcome these limitations and allow for a variety of common stabilized C-nucleophiles, when they are introduced as the corresponding silylated compounds, to undergo enantioselective allylations using allylic fluorides. The reactions of silyl enol ethers afford the allylation products in good yields and with high degree of regio/stereoselectivity as well as diastereoselectivity when cyclic silyl enol ethers are used. Further examples of silylated stabilized carbon nucleophiles that undergo efficient allylation speak in favor of the general applicability of this concept to C-centered nucleophiles.

Risk entanglement and the social relationality of risk.

Relational accounts of risk explain variation in risk perception through situated cognitions defining risk as a relationship between "risk objects" and "objects at risk". We extend this approach to include not only the relational constitution of cognitive risk objects, but also of the different actors assessing risk. Risk in this perspective is relational because it establishes a link between two different cognitive objects and between two (or more) actors. We argue that this is the case when at least two actors refer to a common risk object while retaining distinct objects at risk. We call this a constellation of risk entanglement across actors. We illustrate our theoretical arguments using data from 68 qualitative interviews and ethnographic fieldwork in the German finance-state nexus. Our analyses indicate how risk entanglement affects and transforms the fundamental logics according to which both of these fields operate.

Restoration of insect communities after land use change is shaped by plant diversity: a case study on carabid beetles (Carabidae).

There is no doubt about the insect decline currently taking place in ecosystems with large anthropogenic impacts. Thus, there is a need for practices that avoid insect decline and or help to recover insect communities that have already suffered. Plant diversity has been shown to be positively related to insect abundance and diversity and to ecosystem functions provided by insects. However, it remains open if increased plant diversity can help to recover decreased populations. Here, we tested over one decade the effects of plant diversity on the carabid community in a large grassland biodiversity experiment and how plant diversity fostered the establishment of a natural grassland community after conversion of an arable field. There was a dramatic decline in carabid abundance from 2003, the first year after establishing the diversity experiment, to 2005. However, subsequently, the abundance increased constantly. One year after the land use change most individuals and species were those commonly found in agricultural fields. In subsequent years the community was dominated by grassland species. While plant diversity did not affect the abundance and richness of the carabid community, the turnover to a more native grassland community was accelerated by plant diversity in the first years after the land use change. In contrast, in later years plant diversity stabilized the community assemblage. Our study shows that high plant diversity can contribute to a faster transition of insect populations towards naturally occurring community assemblages and at later stages to more stabilized assemblages.

Increased soil carbon storage through plant diversity strengthens with time and extends into the subsoil.

Soils are important for ecosystem functioning and service provisioning. Soil communities and their functions, in turn, are strongly promoted by plant diversity, and such positive effects strengthen with time. However, plant diversity effects on soil organic matter have mostly been investigated in the topsoil, and there are only very few long-term studies. Thus, it remains unclear if plant diversity effects strengthen with time and to which depth these effects extend. Here, we repeatedly sampled soil to 1 m depth in a long-term grassland biodiversity experiment. We investigated how plant diversity impacted soil organic carbon and nitrogen concentrations and stocks and their stable isotopes 13 C and 15 N, as well as how these effects changed after 5, 10, and 14 years. We found that higher plant diversity increased carbon and nitrogen storage in the topsoil since the establishment of the experiment. Stable isotopes revealed that these increases were associated with new plant-derived inputs, resulting in less processed and less decomposed soil organic matter. In subsoils, mainly the presence of specific plant functional groups drove organic matter dynamics. For example, the presence of deep-rooting tall herbs decreased carbon concentrations, most probably through stimulating soil organic matter decomposition. Moreover, plant diversity effects on soil organic matter became stronger in topsoil over time and reached subsoil layers, while the effects of specific plant functional groups in subsoil progressively diminished over time. Our results indicate that after changing the soil system the pathways of organic matter transfer to the subsoil need time to establish. In our grassland system, organic matter storage in subsoils was driven by the redistribution of already stored soil organic matter from the topsoil to deeper soil layers, for example, via bioturbation or dissolved organic matter. Therefore, managing plant diversity may, thus, have significant implications for subsoil carbon storage and other critical ecosystem services.

Trotter Product Formulae for ∗ -Automorphisms of Quantum Lattice Systems.

We consider the dynamics t ↦ τ t of an infinite quantum lattice system that is generated by a local interaction. If the interaction decomposes into a finite number of terms that are themselves local interactions, we show that τ t can be efficiently approximated by a product of n automorphisms, each of them being an alternating product generated by the individual terms. For any integer m, we construct a product formula (in the spirit of Trotter) such that the approximation error scales as n - m . Our bounds hold in norm, pointwise for algebra elements that are sufficiently well approximated by finite volume observables.

Improving pediatric multiple sclerosis interventional phase III study design: a meta-analysis.

Background: To support innovative trial designs in a regulatory setting for pediatric-onset multiple sclerosis (MS), the study aimed to perform a systematic literature review and meta-analysis of relapse rates with interferon ß (IFN ß), fingolimod, and natalizumab and thereby demonstrate potential benefits of Bayesian and non-inferiority designs in this population. Methods: We conducted a literature search in MEDLINE and EMBASE from inception until 17 June 2020 of all studies reporting annualized relapse rates (ARR) in IFN ß-, fingolimod-, or natalizumab-treated patients with pediatric-onset relapsing-remitting MS. These interventions were chosen because the literature was mainly available for these treatments, and they are currently used for the treatment of pediatric MS. Two researchers independently extracted data and assessed study quality using the Cochrane Effective Practice and Organization of Care - Quality Assessment Tool. The meta-analysis estimates were obtained by Bayesian random effects model. Data were summarized as ARR point estimates and 95% credible intervals. Results: We found 19 articles, including 2 randomized controlled trials. The baseline ARR reported was between 1.4 and 3.7. The meta-analysis-based ARR was significantly higher in IFN ß-treated patients (0.69, 95% credible interval: 0.51-0.91) versus fingolimod (0.11, 0.04-0.27) and natalizumab (0.17, 0.09-0.31). Based on the meta-analysis results, an appropriate non-inferiority margin versus fingolimod could be in the range of 2.29-2.67 and for natalizumab 1.72-2.29 on the ARR ratio scale. A Bayesian design, which uses historical information for a fingolimod or natalizumab control arm, could reduce the sample size of a new trial by 18 or 14 patients, respectively. Conclusion: This meta-analysis provides evidence that relapse rates are considerably higher with IFNs versus fingolimod or natalizumab. The results support the use of innovative Bayesian or non-inferiority designs to avoid exposing patients to less effective comparators in trials and bringing new medications to patients more efficiently.

Risk Entanglement in the Finance-State Nexus: The Case of Systemic and Political Risk.

Crises such as European debt crisis, Brexit, and COVID-19 have challenged established relations between finance and the state in attempts at mitigating a broad range of crises-related risks. We ask whether and how these altered relations in themselves constitute novel uncertainties and risks between the two fields. To better understand these dynamics, we introduce the concept of "risk entanglement" to complement financialization as a key concept presently capturing these relations. Based on qualitative research in the German finance-state nexus, we show how financial and state actors mutually construe each other as risks that need to be managed and mitigated to safeguard their particular, field-specific logics and ends. We focus on systemic risk and political risk as two cases of risk entanglement: whereas systemic risk reflects the threat of a potential financial meltdown to the state, political risk reflects how the state endangers established risk practices in finance.

Eliciting judgements about dependent quantities of interest: The SHeffield ELicitation Framework extension and copula methods illustrated using an asthma case study.

Pharmaceutical companies regularly need to make decisions about drug development programs based on the limited knowledge from early stage clinical trials. In this situation, eliciting the judgements of experts is an attractive approach for synthesising evidence on the unknown quantities of interest. When calculating the probability of success for a drug development program, multiple quantities of interest-such as the effect of a drug on different endpoints-should not be treated as unrelated. We discuss two approaches for establishing a multivariate distribution for several related quantities within the SHeffield ELicitation Framework (SHELF). The first approach elicits experts' judgements about a quantity of interest conditional on knowledge about another one. For the second approach, we first elicit marginal distributions for each quantity of interest. Then, for each pair of quantities, we elicit the concordance probability that both lie on the same side of their respective elicited medians. This allows us to specify a copula to obtain the joint distribution of the quantities of interest. We show how these approaches were used in an elicitation workshop that was performed to assess the probability of success of the registrational program of an asthma drug. The judgements of the experts, which were obtained prior to completion of the pivotal studies, were well aligned with the final trial results.

A New Comprehensive Approach to Assess the Probability of Success of Development Programs Before Pivotal Trials.

The point at which clinical development programs transition from early phase to pivotal trials is a critical milestone. Substantial uncertainty about the outcome of pivotal trials may remain even after seeing positive early phase data, and companies may need to make difficult prioritization decisions for their portfolio. The probability of success (PoS) of a program, a single number expressed as a percentage reflecting the multitude of risks that may influence the final program outcome, is a key decision-making tool. Despite its importance, companies often rely on crude industry benchmarks that may be "adjusted" by experts based on undocumented criteria and which are typically misaligned with the definition of success used to drive commercial forecasts, leading to overly optimistic expected net present value calculations. We developed a new framework to assess the PoS of a program before pivotal trials begin. Our definition of success encompasses the successful outcome of pivotal trials, regulatory approval and meeting the requirements for market access as outlined in the target product profile. The proposed approach is organized in four steps and uses an innovative Bayesian approach to synthesize all relevant evidence. The new PoS framework is systematic and transparent. It will help organizations to make more informed decisions. In this paper, we outline the rationale and elaborate on the structure of the proposed framework, provide examples, and discuss the benefits and challenges associated with its adoption.

Improving the assessment of the probability of success in late stage drug development.

There are several steps to confirming the safety and efficacy of a new medicine. A sequence of trials, each with its own objectives, is usually required. Quantitative risk metrics can be useful for informing decisions about whether a medicine should transition from one stage of development to the next. To obtain an estimate of the probability of regulatory approval, pharmaceutical companies may start with industry-wide success rates and then apply to these subjective adjustments to reflect program-specific information. However, this approach lacks transparency and fails to make full use of data from previous clinical trials. We describe a quantitative Bayesian approach for calculating the probability of success (PoS) at the end of phase II which incorporates internal clinical data from one or more phase IIb studies, industry-wide success rates, and expert opinion or external data if needed. Using an example, we illustrate how PoS can be calculated accounting for differences between the phase II data and future phase III trials, and discuss how the methods can be extended to accommodate accelerated drug development pathways.

Above- and belowground biodiversity jointly tighten the P cycle in agricultural grasslands.

Experiments showed that biodiversity increases grassland productivity and nutrient exploitation, potentially reducing fertiliser needs. Enhancing biodiversity could improve P-use efficiency of grasslands, which is beneficial given that rock-derived P fertilisers are expected to become scarce in the future. Here, we show in a biodiversity experiment that more diverse plant communities were able to exploit P resources more completely than less diverse ones. In the agricultural grasslands that we studied, management effects either overruled or modified the driving role of plant diversity observed in the biodiversity experiment. Nevertheless, we show that greater above- (plants) and belowground (mycorrhizal fungi) biodiversity contributed to tightening the P cycle in agricultural grasslands, as reduced management intensity and the associated increased biodiversity fostered the exploitation of P resources. Our results demonstrate that promoting a high above- and belowground biodiversity has ecological (biodiversity protection) and economical (fertiliser savings) benefits. Such win-win situations for farmers and biodiversity are crucial to convince farmers of the benefits of biodiversity and thus counteract global biodiversity loss.

Contrasting responses of above- and belowground diversity to multiple components of land-use intensity.

Land-use intensification is a major driver of biodiversity loss. However, understanding how different components of land use drive biodiversity loss requires the investigation of multiple trophic levels across spatial scales. Using data from 150 agricultural grasslands in central Europe, we assess the influence of multiple components of local- and landscape-level land use on more than 4,000 above- and belowground taxa, spanning 20 trophic groups. Plot-level land-use intensity is strongly and negatively associated with aboveground trophic groups, but positively or not associated with belowground trophic groups. Meanwhile, both above- and belowground trophic groups respond to landscape-level land use, but to different drivers: aboveground diversity of grasslands is promoted by diverse surrounding land-cover, while belowground diversity is positively related to a high permanent forest cover in the surrounding landscape. These results highlight a role of landscape-level land use in shaping belowground communities, and suggest that revised agroecosystem management strategies are needed to conserve whole-ecosystem biodiversity.

Invertebrate Decline Leads to Shifts in Plant Species Abundance and Phenology.

Climate and land-use change lead to decreasing invertebrate biomass and alter invertebrate communities. These biotic changes may affect plant species abundance and phenology. Using 24 controlled experimental units in the iDiv Ecotron, we assessed the effects of invertebrate decline on an artificial grassland community formed by 12 herbaceous plant species. More specifically, we used Malaise traps and sweep nets to collect invertebrates from a local tall oatgrass meadow and included them in our Ecotron units at two different invertebrate densities: 100% (no invertebrate decline) and 25% (invertebrate decline of 75%). Another eight EcoUnits received no fauna and served as a control. Plant species abundance and flowering phenology was observed weekly over a period of 18 weeks. Our results showed that invertebrate densities affected the abundance and phenology of plant species. We observed a distinct species abundance shift with respect to the invertebrate treatment. Notably, this shift included a reduction in the abundance of the dominant plant species, Trifolium pratense, when invertebrates were present. Additionally, we found that the species shifted their flowering phenology as a response to the different invertebrate treatments, e.g. with decreasing invertebrate biomass Lotus corniculatus showed a later peak flowering time. We demonstrated that in addition to already well-studied abiotic drivers, biotic components may also drive phenological changes in plant communities. This study clearly suggests that invertebrate decline may contribute to already observed mismatches between plants and animals, with potential negative consequences for ecosystem services like food provision and pollination success. This deterioration of ecosystem function could enhance the loss of insects and plant biodiversity.

The results of biodiversity-ecosystem functioning experiments are realistic.

A large body of research shows that biodiversity loss can reduce ecosystem functioning. However, much of the evidence for this relationship is drawn from biodiversity-ecosystem functioning experiments in which biodiversity loss is simulated by randomly assembling communities of varying species diversity, and ecosystem functions are measured. This random assembly has led some ecologists to question the relevance of biodiversity experiments to real-world ecosystems, where community assembly or disassembly may be non-random and influenced by external drivers, such as climate, soil conditions or land use. Here, we compare data from real-world grassland plant communities with data from two of the largest and longest-running grassland biodiversity experiments (the Jena Experiment in Germany and BioDIV in the United States) in terms of their taxonomic, functional and phylogenetic diversity and functional-trait composition. We found that plant communities of biodiversity experiments cover almost all of the multivariate variation of the real-world communities, while also containing community types that are not currently observed in the real world. Moreover, they have greater variance in their compositional features than their real-world counterparts. We then re-analysed a subset of experimental data that included only ecologically realistic communities (that is, those comparable to real-world communities). For 10 out of 12 biodiversity-ecosystem functioning relationships, biodiversity effects did not differ significantly between the full dataset of biodiversity experiments and the ecologically realistic subset of experimental communities. Although we do not provide direct evidence for strong or consistent biodiversity-ecosystem functioning relationships in real-world communities, our results demonstrate that the results of biodiversity experiments are largely insensitive to the exclusion of unrealistic communities and that the conclusions drawn from biodiversity experiments are generally robust.

Enantioselective Lewis base catalyzed phosphonyldifluoromethylation of allylic fluorides using a C-silyl latent pronucleophile.

The first enantioselective phosphonyldifluoromethylation is enabled by the use of diethyl (difluoro(trimethylsilyl)-methyl)phosphonate reagent as a latent pronucleophile in the Lewis base catalyzed substitution of allylic fluorides. The reaction proceeds as a kinetic resolution to produce both the difluoromethylphosphonate products and the remaining fluorides in good yields and with high stereoselectivity. The use of cinchona based alkaloid catalysts enables the facile synthesis of both enantiomers of the difluoromethylphosphonate products.