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Epidemiology and life history are commonly hypothesized to influence host immune strategy, and the pairwise relationships between immune strategy and each factor have been extensively investigated. But the interaction of these two is rarely considered, despite evidence that this interaction might produce emergent effects on optimal immune strategy. Here we investigate the confluence of epidemiology and life history as it affects immune strategy through a demographically-framed model of sensitivity and specificity in parasite recognition and response. We find that variation in several different life history traits associated with both reproduction and longevity alters optimal immune strategies – but the direction and magnitude of these effects depends on how epidemiological risks vary across life. Drawing on published life history data, we also find that our predictions apply across chordate taxa. Our results shed light on the complex interactions shaping immune strategy and may prove valuable in interpreting empirical results in ecoimmunology.

Some prokaryotes possess CRISPR-Cas systems that provide adaptive immunity to viruses guided by DNA segments called spacers acquired from invading phage. However, the patchy incidence and limited memory breadth of CRISPR-Cas systems suggest that their fitness benefits are offset by costs. Here, we propose that cross-reactive CRISPR targeting can lead to heterologous autoimmunity, whereby foreign spacers guide self-targeting in a spacer-length dependent fashion. Balancing antiviral defense against autoimmunity predicts a scaling relation between spacer length and CRISPR repertoire size. We find evidence for this scaling through comparative analysis of sequenced prokaryotic genomes, and show that this association also holds at the level of CRISPR types. In contrast, the scaling is absent in strains with nonfunctional CRISPR loci. Finally, we demonstrate that stochastic spacer loss can explain variations around the scaling relation, even between strains of the same species. Our results suggest that heterologous autoimmunity is a selective factor shaping the evolution of CRISPR-Cas systems.

The evolution of the adaptive immune system is characterized by changes in the relative abundances of the B- and T-cell clones that make up its repertoires. To fully capture this evolution, we need to describe the complex dynamics of the response to pathogenic and self-antigenic stimulations, as well as the statistics of novel lymphocyte receptors introduced throughout life. Recent experiments, ranging from high-throughput immune repertoire sequencing to quantification of the response to specific antigens, can help us characterize the effective dynamics of the immune response. Here we describe mathematical models informed by experiments that lead to a picture of clonal competition in a highly stochastic context. We discuss how different types of competition, noise, and selection shape the observed clone-size distributions and contrast them with predictions of a neutral theory of clonal evolution. These mathematical models show that memory and effector immune repertoire evolution is far from neutral and is driven by the history of the pathogenic environment, while naive repertoire dynamics are consistent with neutral evolutionary theory and competition in a fixed antigenic environment. Lastly, we investigate the effect of long-term clonal selection on repertoire aging.

Mitigation measures to reduce indoor transmission of SARS-CoV-2 and other pathogenic microorganisms are urgently needed to combat the current pandemic and to prevent future airborne epidemics or pandemics. Very efficient exhaust filters for nanoparticles down to sizes of only a few nanometers have been available for many years; they are used, for example, in diesel and, more recently, gasoline vehicles to reduce emissions. The size of soot particles emitted by combustion engines, i.e., primary particles and aggregates, includes those of viruses. Therefore, such particle filters should also efficiently remove viruses. This study aimed to design a filter test system with a controlled airflow allowing to aerosolize particles at the aerosol inlet and collect samples before and after the particle filter. As an example, results obtained for the NanoCleaner®, a filter designed to clean cabin air in vehicles, are presented. Validation with soot particles produced with a CAST soot generator revealed a filter efficiency higher than 99.5%. To assess the relevance of the test filter system to measure efficiency for viral particles removal, MS2 bacteriophages, also called Escherichia virus MS2, were used as virus surrogate and aerosolized into the filter test system with the commercially available Emser nebulizer. Filter efficiencies of more than 99% for MS2 bacteriophages were achieved using the NanoCleaner® in the filter test system. Experiments with ceramic wall-flow filters showed similar results. To enlighten the versatility of the filter test system, a typical aircraft cabin air filter was also characterized. The measurements confirmed the high filter efficiency, and in addition, we show a decrease of bacteriophage’s survival on the filter material over 48 h post-exposure. In conclusion, we have established a versatile system that is modular to test any filter system for the efficiency of eliminating MS2 bacteriophages as virus surrogates from air.

Pausing of transcribing RNA polymerase is regulated and creates opportunities to control gene expression. Research in metazoans has so far mainly focused on RNA polymerase II (Pol II) promoter-proximal pausing leaving the pervasive nature of pausing and its regulatory potential in mammalian cells unclear. Here, we developed a pause detecting algorithm (PDA) for nucleotide-resolution occupancy data and a new native elongating transcript sequencing approach, termed nested NET-seq, that strongly reduces artifactual peaks commonly misinterpreted as pausing sites. Leveraging PDA and nested NET-seq reveal widespread genome-wide Pol II pausing at single-nucleotide resolution in human cells. Notably, the majority of Pol II pauses occur outside of promoter-proximal gene regions primarily along the gene-body of transcribed genes. Sequence analysis combined with machine learning modeling reveals DNA sequence properties underlying widespread transcriptional pausing including a new pause motif. Interestingly, key sequence determinants of RNA polymerase pausing are conserved between human cells and bacteria. These studies indicate pervasive sequence-induced transcriptional pausing in human cells and the knowledge of exact pause locations implies potential functional roles in gene expression.

Summary Despite the continuous discovery of new transcript isoforms, fueled by the recent increase in accessibility and accuracy of long-read RNA sequencing data, functional differences between isoforms originating from the same gene often remain obscure. To address this issue and enable researchers to assess potential functional consequences of transcript isoform variation on the proteome, we developed IsoTV. IsoTV is a versatile pipeline to process, predict and visualize the functional features of translated transcript isoforms. Attributes such as gene and isoform expression, transcript composition and functional features are summarized in an easy-to-interpret visualization. IsoTV is able to analyze a variety of data types from all eukaryotic organisms, including short- and long-read RNA-seq data. Using Oxford Nanopore long read data, we demonstrate that IsoTV facilitates the understanding of potential protein isoform function in different cancer cell types. Availability and implementation IsoTV is available at https://github.molgen.mpg.de/MayerGroup/IsoTV, with the corresponding documentation at https://isotv.readthedocs.io/. Supplementary information Supplementary data are available at Bioinformatics online.

Regulatory T cells (Tregs) play a crucial role in mediating immune response. Yet an algorithmic understanding of the role of Tregs in adaptive immunity remains lacking. Here, we present a biophysically realistic model of Treg mediated self-tolerance in which Tregs bind to self-antigens and locally inhibit the proliferation of nearby activated T cells. By exploiting a duality between ecological dynamics and constrained optimization, we show that Tregs tile the potential antigen space while simultaneously minimizing the overlap between Treg activation profiles. We find that for sufficiently high Treg diversity, Treg mediated self-tolerance is robust to fluctuations in self-antigen concentrations but lowering the Treg diversity results in a sharp transition -- related to the Gardner transition in perceptrons -- to a regime where changes in self-antigen concentrations can result in an auto-immune response. We propose a novel experimental test of this transition in immune-deficient mice and discuss potential implications for autoimmune diseases., Comment: 8 pages, 4 figures + Appendix; Accepted at PNAS

Surface treatment intensity monitoring is still an open and challenging nondestructive testing problem. For the estimation of residual stress with ultrasonic measurements, local linear and nonlinear elastic constants are needed as input. In this paper, nonlinear elastic-wave interactions (also called wave mixing or scattering) — namely, the generation of secondary ultrasonic waves in a nonlinear medium — are considered as a prospective means for near-surface nonlinear elastic parameter evaluation. The allowed interactions between bulk and surface waves, as well as the dependence of the scattering efficiency on the frequency and angle between source waves, were investigated through an analytical model, then compared with FEM simulations and experimental results. Finally, possible future steps for the development of the applied methods for the determination of near-surface higher-order elastic constants are discussed. In addition, several problem-relevant data processing procedures are presented.

Global food systems contribute to climate change, the transgression of planetary boundaries and deforestation. An improved understanding of the environmental impacts of different food system futures is crucial for forging strategies to sustainably nourish a growing world population.We here quantify the greenhouse gas (GHG) emissions of global food systemscenarios within a biophysically feasible “option space” in 2050 comprising all scenarios inwhich biomass supply – calculated as function of agricultural area and yields – is sufficient to cover biomass demand – derived fromhuman diets and the feed demand of livestock.We assessed the biophysical feasibility of 520 scenarios in a hypothetical no-deforestation world. For all feasible scenarios, we calculate (in) direct GHG emissions related to agriculture. We also include (possibly negative) GHG emissions fromland-use change, including changes in soil organic carbon (SOC) and carbon sinks fromvegetation regrowth on land spared from food production.We identify 313 of 520 scenarios as feasible. Agricultural GHG emissions (excluding land use change) of feasible scenarios range from 1.7 to 12.5 Gt CO2e yr−1. When including changes in SOC and vegetation regrowth on spare land, the range is between−10.7 and 12.5 Gt CO2e yr−1. Our results show that diets are the main determinant of GHG emissions, with highest GHG emissions found for scenarios including high meat demand, especially if focused on ruminant meat and milk, and lowest emissions for scenarios with vegan diets. Contrary to frequent claims, our results indicate that diets and the composition and quantity of livestock feed, not crop yields, are the strongest determinants of GHG emissions from food-systems when existing forests are to be protected.

The circular economy is a rapidly emerging concept promoted as transformative approach towards sustainable resource use within Planetary Boundaries. It is gaining traction with policymakers, industry and academia worldwide. It promises to slow, narrow and close socioeconomic material cycles by retaining value as long as possible, thereby minimizing primary resource use, waste and emissions. Herein, we utilize a sociometabolic systems approach to investigate the global economy as embedded into a materially closed “spaceship earth” and to scrutinize the development of circularity during industrialization. We quantify primary material and energy inputs into the economy, as well as all outputs to the environment from 1900-2015. The assessment includes two fundamental cycles: a socioeconomic cycle of secondary materials from end-of-life waste and an ecological cycle in which resulting waste and emissions are assessed against regenerative capacities of biogeochemical systems. In a first approximation, we consider only the carbon-neutral fraction of biomass as renewable. We find that from 1900-2015, socioeconomic and ecological input cycling rates decreased from 43% (41-51%) to 27% (25-30%), while non-circular inputs increased 16-fold and non-circular outputs 10-fold. The contribution of ecological cycling to circularity declined from 91% to 76%. We conclude that realizing the transformative potential of the circular economy necessitates addressing four key challenges by research and policy: tackling the growth of material stocks, defining clear criteria for ecological cycling and eliminating unsustainable biomass production, integrating the decarbonization of the energy system with the circular economy and prioritizing absolute reductions of non-circular flows over maximizing (re)cyclingrates.

The adaptive immune system responds to pathogens by selecting clones of cells with specific receptors. While clonal selection in response to particular antigens has been studied in detail, it is unknown how a lifetime of exposures to many antigens collectively shape the immune repertoire. Here, using mathematical modeling and statistical analyses of T cell receptor sequencing data, we develop a quantitative theory of human T cell dynamics compatible with the statistical laws of repertoire organization. We find that clonal expansions during a perinatal time window leave a long-lasting imprint on the human T cell repertoire, which is only slowly reshaped by fluctuating clonal selection during adult life. Our work provides a mechanism for how early clonal dynamics imprint the hierarchy of T cell clone sizes with implications for pathogen defense and autoimmunity., eLife digest The human immune system develops a memory of pathogens that it encounters over its lifetime, allowing it to respond quickly to future infections. It does this partly through T cells, white blood cells that can recognize different pathogens. During an infection, the T cells that recognize the specific pathogen attacking the body will divide until a large number of clones of these T cells is available to help in the fight. After the infection clears, the immune system ‘keeps’ some of these cells so it can recognize the pathogen in the future, and respond quicker to an infection. Over the course of their lives, people will be infected by many different pathogens, leading to a wide variety of T cells that each respond to one of these pathogens. However, it is not well understood how various infections throughout the human lifespan shape the overall population of different T cells. Gaimann et al. used mathematical modelling to study how the composition of the immune system changes in people of different ages. Different populations of T cells – each specialized against a specific antigen – had been previously identified through genetic sequencing. Gaimann et al. analyzed their dynamics to show that many of the largest populations originate around birth, during the formation of the immune system. These findings suggest a potential mechanism for how exposure to pathogens in infancy can influence the immune system much later in life. The results may also explain variations in how people respond to infections and in their risk of developing autoimmune conditions. This understanding could help develop new treatments or interventions to guide the immune system as it develops.

Land use and climate change are important drivers of environmental change and pose a major threat to ecosystems. Although systemic feedbacks between climate and land use changes are expected to have important impacts, research has rarely focused on the interaction between the two drivers. One reason for this could be that forecasts of land use are hardly available on suitable spatial and thematic scales. Agent-based models (ABMs) represent a potentially powerful tool for creating thematic and spatially fine-grained land use scenarios. In order to derive such scenarios, the complex interaction between land users (e.g. farmers) and the broader socio-economic context in which they operate must be taken into account. On landscape to regional scales, agent-based modelling (ABM) is one way to adequately consider these intricacies. ABMs simulate human decisions, and with individual land owners/users as agents, they can simulate usage paths for individual plots of land in thematically fine resolution. Ideally, these simulations are based on an understanding of how farmers make decisions, including anticipated strategies, adaptive behavior and social interactions. In order to develop such an understanding, participatory approaches are useful because they incorporate stakeholders' perspectives into the model calibration, thereby taking into account culture and traditions that often play an important role in land use decisions. A greater proximity to stakeholder perspectives also increases the political relevance of such land use models. Here we present an example where we developed an ABM (SECLAND) parameterised for 1,329 stakeholders, mostly farmers, in the LTSER region Eisenwurzen (Austria) and simulate the changes in land use patterns resulting from their response to three scenarios of changing socio-economic conditions. Summarized in broad categories, the study region currently consists of 67% deciduous and coniferous forests (including logging), 19% grassland, 9% agricultural land and 6% alpine areas. SECLAND simulated small to moderate changes in these percentages until 2050, with little difference between the scenarios. In general, an increase in forests is predicted at the expense of grasslands. The size of agricultural land remains approximately constant. At the level of the 22 land use classes, the trends between the land use change scenarios differ more strongly. This ABM at the individual or farm level is combined with biodiversity and biogeochemical models that analyse how landowners' decision-making affects various ecosystem parameters. We conclude that agent-based modelling is a powerful tool for integrating land use and climate effects into ecosystem projections, especially at regional level.

Zusammenfassung Der Artikel führt in die Verwendung des Mentalisierungskonzepts im Bereich der Frühpädagogik ein und argumentiert, dass es auch in der Arbeit mit geflüchteten Familien hilfreiche Anregungen liefern kann. Mentalisierung wird dabei als zentrales Element des Beziehungsgeschehens und einer entwicklungsförderlichen Beziehungsarbeit in der Frühpädagogik verstanden. Aufgrund ihrer Betonung von Offenheit, Neugier und (Selbst-)Reflexivität bietet eine mentalisierungsbasierte Haltung auch in der Arbeit mit traumatisierten Kindern und Familien mit unterschiedlichem kulturellen Hintergrund eine erste Orientierung. Unter Stress kann die Fähigkeit zur Mentalisierung jedoch verloren gehen oder Verzerrungen unterliegen. Deshalb werden nach einigen grundlegenden Informationen zur Psychotraumatologie und kulturellen Einflüssen auf Entwicklung vor allem Beispiele in den Blick genommen, die deutlich machen, wie die Auseinandersetzung mit traumatisierten Kindern und Familien sowie die Begegnung mit kulturellen Unterschieden die Mentalisierungsfähigkeit von Fachkräften beeinträchtigen kann.

Biological transmission of vesicular content occurs by opening of a fusion pore. Recent experimental observations have illustrated that fusion pores between vesicles that are docked by an extended flat contact zone are located at the edge (vertex) of this zone. We modeled this experimentally observed scenario by coarse-grained molecular simulations and elastic theory. This revealed that fusion pores experience a direct attraction toward the vertex. The size adopted by the resulting vertex pore strongly depends on the apparent contact angle between the adhered vesicles even in the absence of membrane surface tension. Larger contact angles substantially increase the equilibrium size of the vertex pore. Because the cellular membrane fusion machinery actively docks membranes, it facilitates a collective expansion of the contact zone and increases the contact angle. In this way, the fusion machinery can drive expansion of the fusion pore by free energy equivalents of multiple tens of k B T from a distance and not only through the fusion proteins that reside within the fusion pore.

Climate and land‐use change jointly affect the future of biodiversity. Yet, biodiversity scenarios have so far concentrated on climatic effects because forecasts of land use are rarely available at appropriate spatial and thematic scales. Agent‐based models (ABMs) represent a potentially powerful but little explored tool for establishing thematically and spatially fine‐grained land‐use scenarios. Here, we use an ABM parameterized for 1,329 agents, mostly farmers, in a Central European model region, and simulate the changes to land‐use patterns resulting from their response to three scenarios of changing socio‐economic conditions and three scenarios of climate change until the mid of the century. Subsequently, we use species distribution models to, first, analyse relationships between the realized niches of 832 plant species and climatic gradients or land‐use types, respectively, and, second, to project consequent changes in potential regional ranges of these species as triggered by changes in both the altered land‐use patterns and the changing climate. We find that both drivers determine the realized niches of the studied plants, with land use having a stronger effect than any single climatic variable in the model. Nevertheless, the plants' future distributions appear much more responsive to climate than to land‐use changes because alternative future socio‐economic backgrounds have only modest impact on land‐use decisions in the model region. However, relative effects of climate and land‐use changes on biodiversity may differ drastically in other regions, especially where landscapes are still dominated by natural or semi‐natural habitat. We conclude that agent‐based modelling of land use is able to provide scenarios at scales relevant to individual species distribution and suggest that coupling ABMs with models of species' range change should be intensified to provide more realistic biodiversity forecasts., Land‐use and climate change will have important effects on the future of biodiversity. We predict changes to the potential distribution of vascular plants in response to these two drivers in a region of the Austrian Alps. We therefore combine agent‐based modelling of land owners' decisions with species distribution modelling. We find that both drivers determine the realized niches of the studied plants, with land use having a stronger effect than any single climatic variable in the model. Nevertheless, the plants' future distributions appear more responsive to climate than to land‐use changes.

Als der englische Dichter W. H. Auden 1939 kurz nach Freuds Tod im Londoner Exil ein Gedicht zu seinem Gedächtnis verfasste, wählte er den Vergleich mit dem Wetter. Der Name Freud bezeichne weniger eine Person als ein «Meinungsklima», unter dessen Einfluss wir unsere verschiedenen Leben führen: «if often he was wrong and, at times, absurd, to us he is no more a person now but a whole climate of opinion under whom we conduct our different lives» Audens Bild von einem diffusen und unpersönlichen Meinungsklima, in dem die Psychoanalyse allgegenwärtig wurde, steht allerdings in Kontrast zu dem Umstand, dass deren Theorien und Verfahren dauerhaft mit der Persönlichkeit ihres Autors verknüpft blieben. Im Gegensatz zu anderen Wissenschaften wird die Psychoanalyse trotz ihrer vielfältigen Ausprägungen auch noch viele Jahrzehnte nach dem Tod ihres Begründers hauptsächlich mit dessen Namen und Person verbunden.

A mixed signal transmit (TX)-interference cancellation technique targeting Long Term Evolution (LTE) carrier aggregation (CA) receivers is proposed. The introduced architecture aims for the mitigation of TX modulated spur interference, a newly arisen issue in LTE-CA receivers. The resulting technique directly senses the TX leakage within the receiver and generates a reference signal to cancel the TX interference in the digital domain. This architecture benefits from combining the robustness of digital cancellation and the simplicity of analog cancellation. A widely linear least mean squares filter based digital cancellation architecture is proposed to compensate both the main and image spur interference. For a proof of concept, the proposed technique is evaluated on a hardware demonstrator comprising an RFIC with an LTE-CA receiver. Measurement results show that the TX modulated spur interference is suppressed significantly, thereby improving the noise figure (NF) of the receiver by 11.2 dB. The proposed cancellation restores the NF of the receiver to values within 0.1 dB from its value in the absence of the modulated spur.

In The Interpretation of Dreams, Freud refers several times to Artemidorus’s dream book Oneirocritica dating back to the second century ce as a precursor of his own book. This article explores the meaning of this reference by analysing the interrelations between philological scholarship and emerging psychoanalysis in late nineteenth-century Vienna. Freud's own reading of Artemidorus’s text developed in a critical dialogue with the work of the Austrian philologist Theodor Gomperz and his student Friedrich S. Krauss, who produced the first modern German translation of the Oneirocritica. The symbolic method of the ancient dream books, adapted by Freud in later editions of The Interpretation of Dreams for sexual symbolism, did however also inspire dissenting interpretations within the early psychoanalytic movement. Freud's turn to sexual folklore and ethnography, embodied by Krauss's later studies, played a strategic role in these conflicts over dream interpretation.

Air pollution exposure, including passenger car emissions, may cause substantial respiratory health effects and cancer death. In western countries, the majority of passenger cars are driven by gasoline fuel. Recently, new motor technologies and ethanol fuels have been introduced to the market, but potential health effects have not been thoroughly investigated. We developed and verified a coculture model composed of bronchial epithelial cells (ECs) and natural killer cells (NKs) mimicking the human airways to compare toxic effects between pure gasoline (E0) and ethanol-gasoline-blend (E85, 85% ethanol, 15% gasoline) exhaust emitted from a flexfuel gasoline car. We drove a steady state cycle, exposed ECs for 6h and added NKs. We assessed exhaust effects in ECs alone and in cocultures by RT-PCR, flow cytometry, and oxidative stress assay. We found no toxic effects after exposure to E0 or E85 compared to air controls. Comparison between E0 and E85 exposure showed a weak association for less oxidative DNA damage after E85 exposure compared to E0. Our results indicate that short-term exposure to gasoline exhaust may have no major toxic effects in ECs and NKs and that ethanol as part of fuel for gasoline cars may be favorable.

Transcription elongation has emerged as a regulatory hub in gene expression of metazoans. A major control point occurs during early elongation before RNA polymerase II (Pol II) is released into productive elongation. Prior research has linked BRD4 with transcription elongation. Here, we use rapid BET protein and BRD4-selective degradation along with quantitative genome-wide approaches to investigate direct functions of BRD4 in Pol II transcription regulation. Notably, as an immediate consequence of acute BRD4 loss, promoter-proximal pause release is impaired, and transcriptionally engaged Pol II past this checkpoint undergoes readthrough transcription. An integrated proteome-wide analysis uncovers elongation and 3'-RNA processing factors as core BRD4 interactors. BRD4 ablation disrupts the recruitment of general 3'-RNA processing factors at the 5'-control region, which correlates with RNA cleavage and termination defects. These studies, performed in human cells, reveal a BRD4-mediated checkpoint and begin to establish a molecular link between 5'-elongation control and 3'-RNA processing.

Dematerialization at the national level occurs almost exclusively during periods of economic recession or low growth. While recession is not a sustainable strategy to curb environmental impact, such periods may offer important insights on the possibilities of reducing material use. Economic recession research has focused on the interactions between macroeconomic and financial variables with little systematic research dedicated to uncovering how resource use develops during periods of recession. Using a dynamic panel model, we investigate whether and to what extent material use in a sample of 150 economies between 1970 and 2010 was affected by recession and low growth. Recession occurred most frequently and in more than two thirds of all countries during the 1980s and the 1990s. In the 2000s, more than half of the recessions occurred during the financial crisis of 2008. Periods of recession were significantly and negatively correlated with material use - they tended to coincide with dematerialization. Material use decreased in recession years, but the significant correlations with growth in material use became weaker as growth rates increased. Construction minerals and metals, used to build stocks of manufactured capital, reacted more strongly to economic fluctuations than the throughput-dominated flows of biomass and fossil fuels. We conclude that the systematic link between recession and dematerialization can become policy-relevant if the mechanisms causing reductions in material use during these periods are identified.

Membrane fusion in eukaryotic cells mediates the biogenesis of organelles, vesicular traffic between them, and exo- and endocytosis of important signalling molecules, such as hormones and neurotransmitters. Distinct tasks in intracellular membrane fusion have been assigned to conserved protein systems. Tethering proteins mediate the initial recognition and attachment of membranes, whereas SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein complexes are considered as the core fusion engine. SNARE complexes provide mechanical energy to distort membranes and drive them through a hemifusion intermediate towards the formation of a fusion pore. This last step is highly energy-demanding. Here we combine the in vivo and in vitro fusion of yeast vacuoles with molecular simulations to show that tethering proteins are critical for overcoming the final energy barrier to fusion pore formation. SNAREs alone drive vacuoles only into the hemifused state. Tethering proteins greatly increase the volume of SNARE complexes and deform the site of hemifusion, which lowers the energy barrier for pore opening and provides the driving force. Thereby, tethering proteins assume a crucial mechanical role in the terminal stage of membrane fusion that is likely to be conserved at multiple steps of vesicular traffic. We therefore propose that SNAREs and tethering proteins should be considered as a single, non-dissociable device that drives fusion. The core fusion machinery may then be larger and more complex than previously thought.

Le psychanalyste et medecin Wilhelm Reich, reconnu comme pionnier pour ses premiers travaux therapeutiques et sexologiques sur l’orgasme, mais finalement condamne pour sa pretendue decouverte d’une nouvelle energie vitale, « l’orgone », est l’une des figures a la fois marquantes et derangeantes de l’histoire des recherches sur la sexualite. Selon sa fameuse doctrine, l’orgasme constitue la source vitale des individus et des societes entrainant la promesse d’une transformation profonde de celles-ci : c’est par la liberation de la puissance orgasmique qu’adviendra la revolution sexuelle. Cet article propose une approche par l’histoire « concrete » qui permet de comprendre les dispositifs d’experimentation et de traitement de la science reichienne.

Global resource use has been expanding rapidly after 1950 and improved material living conditions and human well-being of large parts of the global population. We here apply a cumulative long-term perspective to gain broader insights into the material requirements of human well-being, the role of trade and the history of environmental pressures than the usual perspective of annual or most recent flows would reveal. Furthermore, we investigate environmental pressures expressed as cumulative extraction per area over the last 60 years. To both ends, we utilize cumulative data on material flows on domestic material inputs (DMI) and domestic extraction (DE) for 148 countries from 1950 - to 2010 and the Social Progress Index. We find that a high level of well-being required at least 460 t/cap of cumulative material inputs from 1950- to 2010. An analysis of the relation between cumulative flows and current human well-being shows statistically significant that at similar levels of cumulative material inputs, biophysical export-orientation of a country has a weak negative influence on well-being. When the Sustainable Development Goals are to be achieved, the scientific community and policy makers have to consider the history of development of resource use to better understand the future challenges ahead.

The free energy of nucleotide hydrolysis depends on phosphate concentration. Cells regulate cytosolic phosphate levels by orchestrating phosphate acquisition and storage through inositol pyrophosphates (PP-InsP) and SPX domains. Here, we report the synthesis of the novel 5-PPP-InsP5 containing a triphosphate subunit. Using this and a series of synthetic PP-InsP, we examined the ligand specificity of the SPX domain in the PP-InsP-controlled yeast polyphosphate polymerase VTC. SPX decodes the relative positioning of the phosphoric anhydrides, their structure (diphosphate vs triphosphate), and the presence of other phosphates on the inositol ring. Despite the higher potency of 1,5-(PP)2-InsP4, 5-PP-InsP5 is the primary activator of VTC in cells, indicating that its higher concentration compensates for its lower potency. 1,5-(PP)2-InsP4 levels rise and could become relevant under stress conditions. Thus, SPX domains may integrate PP-InsP dependent signaling to adapt cytosolic phosphate concentrations to diffe...

The yeast proteome includes about 300 polytopic membrane proteins known or predicted to function as transporters. Such proteins ensure active or passive transport of small ions or metabolites across the plasma or internal membranes. Despite decades of research on yeast transporters, many of these remain uncharacterized in terms of substrate selectivity range, subcellular localization, and biological function. Assaying the uptake of radiolabeled compounds into whole cells or isolated organelles remains a powerful method for characterizing the function and biochemical properties of these proteins. Here we describe established protocols for measuring transporter activity in whole cells, intact vacuoles, or reconstituted vacuolar vesicles. These methods have proved particularly useful in the context of our work on yeast amino acid transporters, and can in principle be applied to assaying the uptake of other categories of compounds.

Summary The concept of a circular economy (CE) is gaining increasing attention from policy makers, industry, and academia. There is a rapidly evolving debate on definitions, limitations, the contribution to a wider sustainability agenda, and a need for indicators to assess the effectiveness of circular economy measures at larger scales. Herein, we present a framework for a comprehensive and economy‐wide biophysical assessment of a CE, utilizing and systematically linking official statistics on resource extraction and use and waste flows in a mass‐balanced approach. This framework builds on the widely applied framework of economy‐wide material flow accounting and expands it by integrating waste flows, recycling, and downcycled materials. We propose a comprehensive set of indicators that measure the scale and circularity of total material and waste flows and their socioeconomic and ecological loop closing. We applied this framework in the context of monitoring efforts for a CE in the European Union (EU28) for the year 2014. We found that 7.4 gigatons (Gt) of materials were processed in the EU and only 0.71 Gt of them were secondary materials. The derived input socioeconomic cycling rate of materials was therefore 9.6%. Further, of the 4.8 Gt of interim output flows, 14.8% were recycled or downcycled. Based on these findings and our first efforts in assessing sensitivity of the framework, a number of improvements are deemed necessary: improved reporting of wastes, explicit modeling of societal in‐use stocks, introduction of criteria for ecological cycling, and disaggregated mass‐based indicators to evaluate environmental impacts of different materials and circularity initiatives.

In the developing human neocortex, progenitor cells generate diverse cell types prenatally. Progenitor cells and newborn neurons respond to signaling cues, including neurotransmitters. While single-cell RNA sequencing has revealed cellular diversity, physiological heterogeneity has yet to be mapped onto these developing and diverse cell types. By combining measurements of intracellular Ca2+ elevations in response to neurotransmitter receptor agonists and RNA sequencing of the same single cells, we show that Ca2+ responses are cell-type-specific and change dynamically with lineage progression. Physiological response properties predict molecular cell identity and additionally reveal diversitynot captured by single-cell transcriptomics. We find that the serotonin receptor HTR2A selectively activates radial glia cells in the developing human, butnot mouse, neocortex, and inhibiting HTR2A receptorsin human radial glia disrupts the radial glial scaffold. We show highly specific neurotransmittersignaling during neurogenesis in the developing human neocortex and highlight evolutionarilydivergent mechanisms of physiological signaling.

Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems leading to crosstalk between different receptors. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of non-cognate ligands can interfere with the detection of the receptor’s cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the noncognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing.

Here, we consider the problem of aggregation of efficiency and productivity indices. We will summarize some of the existing results and will derive new results for aggregation of Hicks-Moorsteen productivity indices.

Die Einfuhrung des WLTC-Testverfahrens (Worldwide Harmonized Light-Duty Vehicles Test Cycle) und des RDE-Tests (Real Driving Emissions) zieht Konsequenzen bei der Auslegung von Verbrennungsmotoren nach sich. Da der RDE-Test im Alltagsverkehr auf der Strase und somit stochastisch gefahren wird, durfen die Emissionsgrenzwerte im kompletten Betriebsbereich des Motors nicht uberschritten werden.