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The cosmological implications of the Covariant Canonical Gauge Theory of Gravity (CCGG) are investigated. CCGG is a Palatini theory derived from first principles using the canonical transformation formalism in the covariant Hamiltonian formulation. The Einstein-Hilbert theory is thereby extended by a quadratic Riemann-Cartan term in the Lagrangian. Moreover, the requirement of covariant conservation of the stress-energy tensor leads to necessary presence of torsion. In the Friedman universe that promotes the cosmological constant to a time-dependent function, and gives rise to a geometrical correction with the EOS of dark radiation. The resulting cosmology, compatible with the ΛCDM parameter set, encompasses bounce and bang scenarios with graceful exits into the late dark energy era. Testing those scenarios against low-z observations shows that CCGG is a viable theory.
The cosmological implications of the Covariant Canonical Gauge Theory of Gravity (CCGG) are investigated. CCGG is a Palatini theory derived from first principles using the canonical transformation formalism in the covariant Hamiltonian formulation. The Einstein-Hilbert theory is thereby extended by a quadratic Riemann-Cartan term in the Lagrangian. Moreover, the requirement of covariant conservation of the stress-energy tensor leads to necessary presence of torsion. In the Friedman universe that promotes the cosmological constant to a time-dependent function, and gives rise to a geometrical correction with the EOS of dark radiation. The resulting cosmology, compatible with the ΛCDM parameter set, encompasses bounce and bang scenarios with graceful exits into the late dark energy era. Testing those scenarios against low-z observations shows that CCGG is a viable theory.
Aim: Replicate the analysis conducted by Prof. Dr. Alexander W. Schmidt-Catran (Goethe University Frankfurt), Prof. Dr. Malcolm Fairbrother (Umea University), and Prof. Dr. Hans-Jürgen Andreß (University of Cologne) that was published in a special issue on Cross-National Comparative Research in the German academic journal Kölner Zeitschrift für Soziologie und Sozialpsychologie in 2019. Result: Almost all calculations, tables and graphs from Schmidt-Catran et al. (2019) could be replicated sufficiently well in R.
MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3' untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3’ untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
Key Points:
* Deep profiling identifies novel targets of miR-181 associated with global gene regulation.
* miR-181 MREs in repeat elements in the coding sequence act through translational inhibition.
* High-resolution analysis reveals an alternative seed match in functional MREs.
MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3' untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
In this paper, we investigate the usefulness of a wide range of features for their usefulness in the resolution of nominal coreference, both as hard constraints (i.e. completely removing elements from the list of possible candidates) as well as soft constraints (where a cumulation of violations of soft constraints will make it less likely that a candidate is chosen as the antecedent). We present a state of the art system based on such constraints and weights estimated with a maximum entropy model, using lexical information to resolve cases of coreferent bridging.
When a statistical parser is trained on one treebank, one usually tests it on another portion of the same treebank, partly due to the fact that a comparable annotation format is needed for testing. But the user of a parser may not be interested in parsing sentences from the same newspaper all over, or even wants syntactic annotations for a slightly different text type. Gildea (2001) for instance found that a parser trained on the WSJ portion of the Penn Treebank performs less well on the Brown corpus (the subset that is available in the PTB bracketing format) than a parser that has been trained only on the Brown corpus, although the latter one has only half as many sentences as the former. Additionally, a parser trained on both the WSJ and Brown corpora performs less well on the Brown corpus than on the WSJ one. This leads us to the following questions that we would like to address in this paper: - Is there a difference in usefulness of techniques that are used to improve parser performance between the same-corpus and the different-corpus case? - Are different types of parsers (rule-based and statistical) equally sensitive to corpus variation? To achieve this, we compared the quality of the parses of a hand-crafted constraint-based parser and a statistical PCFG-based parser that was trained on a treebank of German newspaper text.
Using a qualitative analysis of disagreements from a referentially annotated newspaper corpus, we show that, in coreference annotation, vague referents are prone to greater disagreement. We show how potentially problematic cases can be dealt with in a way that is practical even for larger-scale annotation, considering a real-world example from newspaper text.
In this paper, we argue that difficulties in the definition of coreference itself contribute to lower inter-annotator agreement in certain cases. Data from a large referentially annotated corpus serves to corroborate this point, using a quantitative investigation to assess which effects or problems are likely to be the most prominent. Several examples where such problems occur are discussed in more detail, and we then propose a generalisation of Poesio, Reyle and Stevenson’s Justified Sloppiness Hypothesis to provide a unified model for these cases of disagreement and argue that a deeper understanding of the phenomena involved allows to tackle problematic cases in a more principled fashion than would be possible using only pre-theoretic intuitions.
Distributional approximations to lexical semantics are very useful not only in helping the creation of lexical semantic resources (Kilgariff et al., 2004; Snow et al., 2006), but also when directly applied in tasks that can benefit from large-coverage semantic knowledge such as coreference resolution (Poesio et al., 1998; Gasperin and Vieira, 2004; Versley, 2007), word sense disambiguation (Mc- Carthy et al., 2004) or semantical role labeling (Gordon and Swanson, 2007). We present a model that is built from Webbased corpora using both shallow patterns for grammatical and semantic relations and a window-based approach, using singular value decomposition to decorrelate the feature space which is otherwise too heavily influenced by the skewed topic distribution of Web corpora.
We adopt Markert and Nissim (2005)’s approach of using the World Wide Web to resolve cases of coreferent bridging for German and discuss the strength and weaknesses of this approach. As the general approach of using surface patterns to get information on ontological relations between lexical items has only been tried on English, it is also interesting to see whether the approach works for German as well as it does for English and what differences between these languages need to be accounted for. We also present a novel approach for combining several patterns that yields an ensemble that outperforms the best-performing single patterns in terms of both precision and recall.
In the past, a divide could be seen between ’deep’ parsers on the one hand, which construct a semantic representation out of their input, but usually have significant coverage problems, and more robust parsers on the other hand, which are usually based on a (statistical) model derived from a treebank and have larger coverage, but leave the problem of semantic interpretation to the user. More recently, approaches have emerged that combine the robustness of datadriven (statistical) models with more detailed linguistic interpretation such that the output could be used for deeper semantic analysis. Cahill et al. (2002) use a PCFG-based parsing model in combination with a set of principles and heuristics to derive functional (f-)structures of Lexical-Functional Grammar (LFG). They show that the derived functional structures have a better quality than those generated by a parser based on a state-of-the-art hand-crafted LFG grammar. Advocates of Dependency Grammar usually point out that dependencies already are a semantically meaningful representation (cf. Menzel, 2003). However, parsers based on dependency grammar normally create underspecified representations with respect to certain phenomena such as coordination, apposition and control structures. In these areas they are too "shallow" to be directly used for semantic interpretation. In this paper, we adopt a similar approach to Cahill et al. (2002) using a dependency-based analysis to derive functional structure, and demonstrate the feasibility of this approach using German data. A major focus of our discussion is on the treatment of coordination and other potentially underspecified structures of the dependency data input. F-structure is one of the two core levels of syntactic representation in LFG (Bresnan, 2001). Independently of surface order, it encodes abstract syntactic functions that constitute predicate argument structure and other dependency relations such as subject, predicate, adjunct, but also further semantic information such as the semantic type of an adjunct (e.g. directional). Normally f-structure is captured as a recursive attribute value matrix, which is isomorphic to a directed graph representation. Figure 5 depicts an example target f-structure. As mentioned earlier, these deeper-level dependency relations can be used to construct logical forms as in the approaches of van Genabith and Crouch (1996), who construct underspecified discourse representations (UDRSs), and Spreyer and Frank (2005), who have robust minimal recursion semantics (RMRS) as their target representation. We therefore think that f-structures are a suitable target representation for automatic syntactic analysis in a larger pipeline of mapping text to interpretation. In this paper, we report on the conversion from dependency structures to fstructure. Firstly, we evaluate the f-structure conversion in isolation, starting from hand-corrected dependencies based on the TüBa-D/Z treebank and Versley (2005)´s conversion. Secondly, we start from tokenized text to evaluate the combined process of automatic parsing (using Foth and Menzel (2006)´s parser) and f-structure conversion. As a test set, we randomly selected 100 sentences from TüBa-D/Z which we annotated using a scheme very close to that of the TiGer Dependency Bank (Forst et al., 2004). In the next section, we sketch dependency analysis, the underlying theory of our input representations, and introduce four different representations of coordination. We also describe Weighted Constraint Dependency Grammar (WCDG), the dependency parsing formalism that we use in our experiments. Section 3 characterises the conversion of dependencies to f-structures. Our evaluation is presented in section 4, and finally, section 5 summarises our results and gives an overview of problems remaining to be solved.
Dual coding theories of knowledge suggest that meaning is represented in the brain by a double code, which comprises language-derived representations in the Anterior Temporal Lobe and sensory-derived representations in perceptual and motor regions. This approach predicts that concrete semantic features should activate both codes, whereas abstract features rely exclusively on the linguistic code. Using magnetoencephalography (MEG), we adopted a temporally resolved multiple regression approach to identify the contribution of abstract and concrete semantic predictors to the underlying brain signal. Results evidenced early involvement of anterior-temporal and inferior-frontal brain areas in both abstract and concrete semantic information encoding. At later stages, occipito-temporal regions showed greater responses to concrete compared to abstract features. The present findings shed new light on the temporal dynamics of abstract and concrete semantic representations in the brain and suggest that the concreteness of words processed first with a transmodal/linguistic code, housed in frontotemporal brain systems, and only after with an imagistic/sensorimotor code in perceptual and motor regions.
Dendritic spines are considered a morphological proxy for excitatory synapses, rendering them a target of many different lines of research. Over recent years, it has become possible to image simultaneously large numbers of dendritic spines in 3D volumes of neural tissue. In contrast, currently no automated method for spine detection exists that comes close to the detection performance reached by human experts. However, exploiting such datasets requires new tools for the fully automated detection and analysis of large numbers of spines. Here, we developed an efficient analysis pipeline to detect large numbers of dendritic spines in volumetric fluorescence imaging data. The core of our pipeline is a deep convolutional neural network, which was pretrained on a general-purpose image library, and then optimized on the spine detection task. This transfer learning approach is data efficient while achieving a high detection precision. To train and validate the model we generated a labelled dataset using five human expert annotators to account for the variability in human spine detection. The pipeline enables fully automated dendritic spine detection and reaches a near human-level detection performance. Our method for spine detection is fast, accurate and robust, and thus well suited for large-scale datasets with thousands of spines. The code is easily applicable to new datasets, achieving high detection performance, even without any retraining or adjustment of model parameters.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.
Weak function word shift
(2004)
The fact that object shift only affects weak pronouns in mainland Scandinavian is seen as an instance of a more general observation that can be made in all Germanic languages: weak function words tend to avoid the edges of larger prosodic domains. This generalisation has been formulated within Optimality Theory in terms of alignment constraints on prosodic structure by Selkirk (1996) in explaining thedistribution of prosodically strong and weak forms of English functionwords, especially modal verbs, prepositions and pronouns. But a purely phonological account fails to integrate the syntactic licensing conditions for object shift in an appropriate way. The standard semantico-syntactic accounts of object shift, onthe other hand, fail to explain why it is only weak pronouns that undergo object shift. This paper develops an Optimality theoretic model of the syntax-phonology interface which is based on the interaction of syntactic and prosodic factors. The account can successfully be applied to further related phenomena in English and German.
This paper argues for a particular architecture of OT syntax. This architecture hasthree core features: i) it is bidirectional, the usual production-oriented optimisation (called ‘first optimisation’ here) is accompanied by a second step that checks the recoverability of an underlying form; ii) this underlying form already contains a full-fledged syntactic specification; iii) especially the procedure checking for recoverability makes crucial use of semantic and pragmatic factors. The first section motivates the basic architecture. The second section shows with two examples, how contextual factors are integrated. The third section examines its implications for learning theory, and the fourth section concludes with a broader discussion of the advantages and disadvantages of the proposed model.
This paper is part of a research project on OT Syntax and the typology of the free relative (FR) construction. It concentrates on the details of an OT analysis and some of its consequences for OT syntax. I will not present a general discussion of the phenomenon and the many controversial issues it is famous for in generative syntax.
The aim of this paper is the exploration of an optimality theoretic architecture for syntax that is guided by the concept of "correspondence": syntax is understood as the mechanism of "translating" underlying representations into a surface form. In minimalism, this surface form is called "Phonological Form" (PF). Both semantic and abstract syntactic information are reflected by the surface form. The empirical domain where this architecture is tested are minimal link effects, especially in the case of "wh"-movement. The OT constraints require the surface form to reflect the underlying semantic and syntactic representations as maximally as possible. The means by which underlying relations and properties are encoded are precedence, adjacency, surface morphology and prosodic structure. Information that is not encoded in one of these ways remains unexpressed, and gets lost unless it is recoverable via the context. Different kinds of information are often expressed by the same means. The resulting conflicts are resolved by the relative ranking of the relevant correspondence constraints.
The argument that I tried to elaborate on in this paper is that the conceptual problem behind the traditional competence/performance distinction does not go away, even if we abandon its original Chomskyan formulation. It returns as the question about the relation between the model of the grammar and the results of empirical investigations – the question of empirical verification The theoretical concept of markedness is argued to be an ideal correlate of gradience. Optimality Theory, being based on markedness, is a promising framework for the task of bridging the gap between model and empirical world. However, this task not only requires a model of grammar, but also a theory of the methods that are chosen in empirical investigations and how their results are interpreted, and a theory of how to derive predictions for these particular empirical investigations from the model. Stochastic Optimality Theory is one possible formulation of a proposal that derives empirical predictions from an OT model. However, I hope to have shown that it is not enough to take frequency distributions and relative acceptabilities at face value, and simply construe some Stochastic OT model that fits the facts. These facts first of all need to be interpreted, and those factors that the grammar has to account for must be sorted out from those about which grammar should have nothing to say. This task, to my mind, is more complicated than the picture that a simplistic application of (not only) Stochastic OT might draw.
The regeneration of hadronic resonances is discussed for heavy ion collisions at SPS and SIS-300 energies. The time evolutions of Delta, rho and phi resonances are investigated. Special emphasize is put on resonance regeneration after chemical freeze-out. The emission time spectra of experimentally detectable resonances are explored.
We predict transverse and longitudinal momentum spectra and yields of rho 0 and omega mesons reconstructed from hadron correlations in C+C reactions at 2~AGeV. The rapidity and pT distributions for reconstructable rho 0 mesons differs strongly from the primary distribution, while the omega's distributions are only weakly modified. We discuss the temporal and spatial distributions of the particles emitted in the hadron channel. Finally, we report on the mass shift of the rho 0 due to its coupling to the N*(1520), which is observable in both the di-lepton and pi pi channel. Our calculations can be tested with the Hades experiment at GSI, Darmstadt.
The establishment and maintenance of protected areas(PAs) is viewed as a key action in delivering post-2020 biodiversity targets. PAs often need to meet a multitude of objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation. As available land and conservation funding are limited, optimizing resources by selecting the most beneficial PAs is vital. Here we present a decision support tool that enables a flexible approach to PA selection on a global scale, allowing different conservation objectives to be weighted and prioritized according to user-specified preferences. We apply the tool across 1347 terrestrial PAs and highlight frequent trade-offs among different objectives, e.g., between biodiversity protection and ecosystem integrity. These results indicate that decision makers must usually decide among conflicting objectives. To assist this our decision support tool provides an explicitly value-based approach that can help resolve such conflicts by considering divergent societal and political demands and values.
The establishment and maintenance of protected areas (PAs) is viewed as a key action in delivering post-2020 biodiversity targets. PAs often need to meet multiple objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation, but available land and conservation funding is limited. Therefore, optimizing resources by selecting the most beneficial PAs is vital. Here, we advocate for a flexible and transparent approach to selecting protected areas based on multiple objectives, and illustrate this with a decision support tool on a global scale. The tool allows weighting and prioritization of different conservation objectives according to user-specified preferences, as well as real-time comparison of the selected areas that result from such different priorities. We apply the tool across 1347 terrestrial PAs and highlight frequent trade-offs among different objectives, e.g., between species protection and ecosystem integrity. Outputs indicate that decision makers frequently face trade-offs among conflicting objectives. Nevertheless, we show that transparent decision-support tools can reveal synergies and trade-offs associated with PA selection, thereby helping to illuminate and resolve land-use conflicts embedded in divergent societal and political demands and values.
Ongoing climate change is a major threat to biodiversity and impacts on species distributions and abundances are already evident. Heterogenous responses of species due to varying abiotic tolerances and dispersal abilities have the potential to further amplify or ameliorate these impacts through changes in species assemblages. Here we investigate the impacts of climate change on terrestrial bird distributions and, subsequently, on species richness as well as on different aspects of phylogenetic diversity of species assemblages across the globe. We go beyond previous work by disentangling the potential impacts on assemblage phylogenetic diversity of species gains vs. losses under climate change and compare the projected impacts to randomized assemblage changes.
We show that climate change might not only affect species numbers and composition of global species assemblages but could also have profound impacts on assemblage phylogenetic diversity, which, across extensive areas, differ significantly from random changes. Both the projected impacts on phylogenetic diversity and on phylogenetic structure vary greatly across the globe. Projected increases in the evolutionary history contained within species assemblages, associated with either increasing phylogenetic diversification or clustering, are most frequent at high northern latitudes. By contrast, projected declines in evolutionary history, associated with increasing phylogenetic over-dispersion or homogenisation, are projected across all continents.
The projected widespread changes in the phylogenetic structure of species assemblages show that changes in species richness do not fully reflect the potential threat from climate change to ecosystems. Our results indicate that the most severe changes to the phylogenetic diversity and structure of species assemblages are likely to be caused by species range shifts rather than range reductions and extinctions. Our findings highlight the importance of considering diverse measures in climate impact assessments and the value of integrating species-specific responses into assessments of entire community changes.
Abstract
The endoplasmic reticulum (ER) is a key organelle of membrane biogenesis and crucial for the folding of both membrane and secretory proteins. Sensors of the unfolded protein response (UPR) monitor the unfolded protein load in the ER and convey effector functions for maintaining ER homeostasis. Aberrant compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent activators of the UPR. How the distinct signals from lipid bilayer stress and unfolded proteins are processed by the conserved UPR transducer Ire1 remains unknown. Here, we have generated a functional, cysteine-less variant of Ire1 and performed systematic cysteine crosslinking experiments in native membranes to establish its transmembrane architecture in signaling-active clusters. We show that the transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped configuration independent of the primary cause for ER stress. This suggests that different forms of stress converge in a common, signaling-active transmembrane architecture of Ire1.
Summary
The endoplasmic reticulum (ER) is a hotspot of lipid biosynthesis and crucial for the folding of membrane and secretory proteins. The unfolded protein response (UPR) controls the size and folding capacity of the ER. The conserved UPR transducer Ire1 senses both unfolded proteins and aberrant lipid compositions to mount adaptive responses. Using a biochemical assay to study Ire1 in signaling-active clusters, Väth et al. provide evidence that the neighboring transmembrane helices of clustered Ire1 form an ‘X’ irrespectively of the primary cause of ER stress. Hence, different forms of ER stress converge in a common, signaling-active transmembrane architecture of Ire1.
Bisphenols and phthalates, chemicals frequently used in plastic products, promote obesity in cell and animal models. However, these well-known metabolism disrupting chemicals (MDCs) represent only a minute fraction of all compounds found in plastics. To gain a comprehensive understanding of plastics as a source of exposure to MDCs, we characterized all chemicals present in 34 everyday products using nontarget high-resolution mass spectrometry and analyzed their joint adipogenic activities by high-content imaging. We detected 55,300 chemical features and tentatively identified 629 unique compounds, including 11 known MDCs. Importantly, chemicals that induced proliferation, growth, and triglyceride accumulation in 3T3-L1 adipocytes were found in one third of the products. Since the majority did not target peroxisome proliferator-activated receptor γ, the effects are likely to be caused by unknown MDCs. Our study demonstrates that daily-use plastics contain potent mixtures of MDCs and can, therefore, be a relevant yet underestimated environmental factor contributing to obesity.
Teaser Plastics contain a potent mixture of chemicals promoting adipogenesis, a key process in developing obesity.
With the emergence of immunotherapies, the understanding of functional HLA class I antigen presentation to T cells is more relevant than ever. Current knowledge on antigen presentation is based on decades of research in a wide variety of cell types with varying antigen presentation machinery (APM) expression patterns, proteomes and HLA haplotypes. This diversity complicates the establishment of individual APM contributions to antigen generation, selection and presentation. Therefore, we generated a novel Panel of APM Knockout Cell lines (PAKC) from the same genetic origin. After CRISPR/Cas9 genome-editing of ten individual APM components in a human cell line, we derived clonal cell lines and confirmed their knockout status and phenotype. We then show how PAKC will accelerate research on the functional interplay between APM components and their role in antigen generation and presentation. This will lead to improved understanding of peptide-specific T cell responses in infection, cancer and autoimmunity.
CONCLUSION The analysis of the exposure measurement problem has shown that the proper measurement of counterparty exposure for portfolios of derivatives transactions is a complex task that cannot be performed without making a lot of simplifying assumptions. Because of the complicated interaction of correlation effects and offsettings from different transactions, the single transaction framework which is currently used by most banks is definitely not capable of accurately determining the portfolio credit risk. When simulation techniques are applied to estimate exposure, the accuracy of exposure estimations can be increased significantly. However, a lot of modelling choices has to be made concerning the valuation of transactions and the stochastic model of underlying market rates. Because the system has to make projections of market rates into the far future, the choice of an appropriate stochastic model for market rate dynamics is crucial in order to prevent unreasonable scenarios. The predominant application of models based on Brownian Motion in today’s bank risk management therefore leads to questionable results in respect to derivatives exposure evaluation.
The gradual heterogeneity of climatic factors pose varying selection pressures across geographic distances that leave signatures of clinal variation in the genome. Separating signatures of clinal adaptation from signatures of other evolutionary forces, such as demographic processes, genetic drift, and adaptation to non-clinal conditions of the immediate local environment is a major challenge. Here, we examine climate adaptation in five natural populations of the harlequin fly Chironomus riparius sampled along a climatic gradient across Europe. Our study integrates experimental data, individual genome resequencing, Pool-Seq data, and population genetic modelling. Common-garden experiments revealed a positive correlation of population growth rates corresponding to the population origin along the climate gradient, suggesting thermal adaptation on the phenotypic level. Based on a population genomic analysis, we derived empirical estimates of historical demography and migration. We used an FST outlier approach to infer positive selection across the climate gradient, in combination with an environmental association analysis. In total we identified 162 candidate genes as genomic basis of climate adaptation. Enriched functions among these candidate genes involved the apoptotic process and molecular response to heat, as well as functions identified in other studies of climate adaptation in other insects. Our results show that local climate conditions impose strong selection pressures and lead to genomic adaptation despite strong gene flow. Moreover, these results imply that selection to different climatic conditions seems to converge on a functional level, at least between different insect species.
The ubiquitin (Ub) code denotes the complex Ub architectures, including Ub chains of different length, linkage-type and linkage combinations, which enable ubiquitination to control a wide range of protein fates. Although many linkage-specific interactors have been described, how interactors are able to decode more complex architectures is not fully understood. We conducted a Ub interactor screen, in humans and yeast, using Ub chains of varying length, as well as, homotypic and heterotypic branched chains of the two most abundant linkage types – K48- and K63-linked Ub. We identified some of the first K48/K63 branch-specific Ub interactors, including histone ADP-ribosyltransferase PARP10/ARTD10, E3 ligase UBR4 and huntingtin-interacting protein HIP1. Furthermore, we revealed the importance of chain length by identifying interactors with a preference for Ub3 over Ub2 chains, including Ub-directed endoprotease DDI2, autophagy receptor CCDC50 and p97-adaptor FAF1. Crucially, we compared datasets collected using two common DUB inhibitors – Chloroacetamide and N-ethylmaleimide. This revealed inhibitor-dependent interactors, highlighting the importance of inhibitor consideration during pulldown studies. This dataset is a key resource for understanding how the Ub code is read.
By using the background field method of QCD in a path integral approach, we derive the equation of motion for the classical chromofield and for the gluon in a system containing the gluon and the classical chromofield simul- taneously. This inhomogeneous field equation contains a current term, which is the expectation value of a composite operator including linear, square and cubic terms of the gluon field. We also derive identities which the current should obey from the gauge invariance. We calculate the current at the leading order where the current induced by the gluon is opposite in sign to that induced by the quark. This is just the feature of the non-Abelian gauge field theory which has asymptotic freedom. Physically, the induced current can be treated as the displacement current in the polarized vacuum, and its e ect is equivalent to redefining the field and the coupling constant. PACS: 12.38.-t,12.38.Aw,11.15.-q,12.38.Mh
The non-equilibrium quantum field dynamics is usually described in the closed-time-path formalism. The initial state correlations are introduced into the generating functional by non-local source terms. We propose a functional approach to the Dyson-Schwinger equation, which treats the non-local and local source terms in the same way. In this approach, the generating functional is formulated for the connected Green functions and one-particle-irreducible vertices. The great advantages of our approach over the widely used two-particle-irreducible method are that it is much simpler and that it is easy to implement the procedure in a computer program to automatically generate the Feynman diagrams for a given process. The method is then applied to a pure gluon plasma to derive the gauge-covariant transport equation from the Dyson-Schwinger equation in the background covariant gauge. We discuss the structure of the kinetic equation and show its relationship with the classical one. We derive the gauge-covariant collision part and present an approximation in the vicinity of equilibrium. The role of the non-local source kernel in the non-equilibrium system is discussed in the context of a free scalar field. PACS numbers: 12.38.Mh, 25.75.-q, 24.85.+p, 11.15.Kc
We derive the kinetic equation for pure gluon QCD plasma in a general way, applying the background field method. We show that the quantum kinetic equation contains a term as in the classical case, that describes a color charge precession of partons moving in the gauge field. We emphasize that this new term is necessary for the gauge covariance of the resulting equation.
We derive the quantum kinetic equation for a pure gluon plasma, applying the background field and closed-time-path method. The derivation is more general and transparent than earlier works. A term in the equation is found which, as in the classical case, corresponds to the color charge precession for partons moving in the gauge field. PACS numbers: 12.38.Mh, 25.75.-q, 24.85.+p, 11.15.Kc
We calculate p, ±,K± and (+ 0) rapidity distributions and compare to experimental data from SIS to SPS energies within the UrQMD and HSD transport approaches that are both based on string, quark, diquark (q, ¯q, qq, ¯q ¯q) and hadronic degrees of freedom. The two transport models do not include any explicit phase transition to a quark-gluon plasma (QGP). It is found that both approaches agree rather well with each other and with the experimental rapidity distributions for protons, s, ± and K±. In- spite of this apparent agreement both transport models fail to reproduce the maximum in the excitation function for the ratio K+/ + found experimen- tally between 11 and 40 A·GeV. A comparison to the various experimental data shows that this failure is dominantly due to an insu cient description of pion rapidity distributions rather than missing strangeness . The modest di erences in the transport model results on the other hand can be attributed to di erent implementations of string formation and frag- mentation, that are not su ciently controlled by experimental data for the elementary reactions in vacuum.
We study central collision of Pb + Pb at 20, 40, 80 and 160 A·GeV within the UrQMD transport approach and compare rapidity distributions of ,K+,K and with the recent measurements from the NA49 Collaboration at 40, 80 and 160 A·GeV. It is found that the UrQMD model reasonably describes the data, however, systematically overpredicts the yield by < 20%, whereas the K+ yield is underestimated by < 15%. The K yields are in a good agreement with the experimental data, the yields are also in a reasonable correspondence with the data for all energies. We find that hadronic flavour exchange reactions largely distort the information about the initial strangeness production mechanism at all energies considered. PACS: 25.75.+r
We estimate the energy density epsilon pile-up at mid-rapidity in central Pb+Pb collisions from 2 200 GeV/nucleon. epsilon is decomposed into hadronic and partonic contributions. A detailed analysis of the collision dynamics in the framework of a microscopic transport model shows the importance of partonic degrees of freedom and rescattering of leading (di)quarks in the early phase of the reaction for Elab 30 GeV/nucleon. In Pb+Pb collisions at 160 GeV/nucleon the energy density reaches up to 4 GeV/fm3, 95% of which are contained in partonic degrees of freedom.
The amount of proton stopping in central Pb+Pb collisions from 20 160 A·GeV as well as hyperon and antihyperon rapidity distributions are calcu- lated within the UrQMD model in comparison to experimental data at 40, 80 and 160 A·GeV taken recently from the NA49 collaboration. Further- more, the amount of baryon stopping at 160 A·GeV for Pb + Pb collisions is studied as a function of centrality in comparison to the NA49 data. We find that the strange baryon yield is reasonably described for central colli- sions, however, the rapidity distributions are somewhat more narrow than the data. Moreover, the experimental antihyperon rapidity distributions at 40, 80 and 160 A·GeV are underestimated by up to factors of 3 - depending on the annihilation cross section employed - which might be addressed to missing multi-meson fusion channels in the UrQMD model. PACS 25.75.+r
The European bison was saved from the brink of extinction due to considerable conservation efforts since the early 20th century. The current global population of > 9,500 individuals is the result of successful ex situ breeding based on a stock of only 12 founders, resulting in an extremely low level of genetic variability. Due to the low allelic diversity, traditional molecular tools, such as microsatellites, fail to provide sufficient resolution for accurate genetic assessments in European bison, let alone from non-invasive samples. Here, we present a SNP panel for accurate high-resolution genotyping of European bison, which is suitable for a wide variety of sample types. The panel accommodates 96 markers allowing for individual and parental assignment, sex determination, breeding line discrimination, and cross-species detection. Two applications were shown to be utilisable in further Bos species with potential conservation significance. The new SNP panel will allow to tackle crucial tasks in European bison conservation, including the genetic monitoring of reintroduced populations, and a molecular assessment of pedigree data documented in the world’s first studbook of a threatened species.
How much data do we need? Lower bounds of brain activation states to predict human cognitive ability
(2022)
Human functional brain connectivity can be temporally decomposed into states of high and low cofluctuation, defined as coactivation of brain regions over time. Despite their low frequency of occurrence, states of particularly high cofluctuation have been shown to reflect fundamentals of intrinsic functional network architecture (derived from resting-state fMRI) and to be highly subject-specific. However, it is currently unclear whether such network-defining states of high cofluctuation also contribute to individual variations in cognitive abilities – which strongly rely on the interactions among distributed brain regions. By introducing CMEP, an eigenvector-based prediction framework, we show that functional connectivity estimates from as few as 20 temporally separated time frames (< 3% of a 10 min resting-state fMRI scan) are significantly predictive of individual differences in intelligence (N = 281, p < .001). In contrast and against previous expectations, individual’s network-defining time frames of particularly high cofluctuation do not achieve significant prediction of intelligence. Multiple functional brain networks contribute to the prediction, and all results replicate in an independent sample (N = 831). Our results suggest that although fundamentals of person-specific functional connectomes can be derived from few time frames of highest brain connectivity, temporally distributed information is necessary to extract information about cognitive abilities from functional connectivity time series. This information, however, is not restricted to specific connectivity states, like network-defining high-cofluctuation states, but rather reflected across the entire length of the brain connectivity time series.
Human functional brain connectivity can be temporally decomposed into states of high and low cofluctuation, defined as coactivation of brain regions over time. Rare states of particularly high cofluctuation have been shown to reflect fundamentals of intrinsic functional network architecture and to be highly subject-specific. However, it is unclear whether such network-defining states also contribute to individual variations in cognitive abilities – which strongly rely on the interactions among distributed brain regions. By introducing CMEP, a new eigenvector-based prediction framework, we show that as few as 16 temporally separated time frames (< 1.5% of 10min resting-state fMRI) can significantly predict individual differences in intelligence (N = 263, p < .001). Against previous expectations, individual’s network-defining time frames of particularly high cofluctuation do not predict intelligence. Multiple functional brain networks contribute to the prediction, and all results replicate in an independent sample (N = 831). Our results suggest that although fundamentals of person-specific functional connectomes can be derived from few time frames of highest connectivity, temporally distributed information is necessary to extract information about cognitive abilities. This information is not restricted to specific connectivity states, like network-defining high-cofluctuation states, but rather reflected across the entire length of the brain connectivity time series.
We study the effects of isovector-scalar meson delta on the equation of state (EOS) of neutron star matter in strong magnetic fields. The EOS of neutron-star matter and nucleon effective masses are calculated in the framework of Lagrangian field theory, which is solved within the mean-field approximation. From the numerical results one can find that the delta-field leads to a remarkable splitting of proton and neutron effective masses. The strength of delta-field decreases with the increasing of the magnetic field and is little at ultrastrong field. The proton effective mass is highly influenced by magnetic fields, while the effect of magnetic fields on the neutron effective mass is negligible. The EOS turns out to be stiffer at B < 10^15G but becomes softer at stronger magnetic field after including the delta-field. The AMM terms can affect the system merely at ultrastrong magnetic field(B > 10^19G). In the range of 10^15 G - 10^18 G the properties of neutron-star matter are found to be similar with those without magnetic fields.
Orientation hypercolumns in the visual cortex are delimited by the repeating pinwheel patterns of orientation selective neurons. We design a generative model for visual cortex maps that reproduces such orientation hypercolumns as well as ocular dominance maps while preserving retinotopy. The model uses a neural placement method based on t–distributed stochastic neighbour embedding (t–SNE) to create maps that order common features in the connectivity matrix of the circuit. We find that, in our model, hypercolumns generally appear with fixed cell numbers independently of the overall network size. These results would suggest that existing differences in absolute pinwheel densities are a consequence of variations in neuronal density. Indeed, available measurements in the visual cortex indicate that pinwheels consist of a constant number of ∼30, 000 neurons. Our model is able to reproduce a large number of characteristic properties known for visual cortex maps. We provide the corresponding software in our MAPStoolbox for Matlab.
The ability to vocalize is ubiquitous in vertebrates, but neural networks leading to vocalization production remain poorly understood. Here we performed simultaneous, large scale, neuronal recordings in the frontal cortex and dorsal striatum (caudate nucleus) during the production of echolocation and non-echolocation calls in bats. This approach allows to assess the general aspects underlying vocalization production in mammals and the unique evolutionary adaptations of bat echolocation. Our findings show that distinct intra-areal brain rhythms in the beta (12-30 Hz) and gamma (30-80 Hz) bands of the local field potential can be used to predict the bats’ vocal output and that phase locking between spikes and field potentials occurs prior vocalization production. Moreover, the fronto-striatal network is differentially coupled in the theta-band during the production of echolocation and non-echolocation calls. Overall, our results present evidence for fronto-striatal network oscillations in motor action prediction in mammals.
The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and 2) are major facilitator superfamily transporters from the solute carrier family 49. Dysregulation of these ubiquitous transporters has been linked to various haematological and neurological disorders. While both FLVCRs were initially proposed to hold a physiological function in heme transport, subsequent studies questioned this notion. Here, we used structural, computational and biochemical methods and conclude that these two FLVCRs function as human choline transporters. We present cryo-electron microscopy structures of FLVCRs in different inward- and outward-facing conformations, captured in the apo state or in complex with choline in their translocation pathways. Our findings provide insights into the molecular framework of choline coordination and transport, largely mediated by conserved cation-π interactions, and further illuminate the conformational dynamics of the transport cycle. Moreover, we identified a heme binding site on the protein surface of the FLVCR2 N-domain, and observed that heme actively drives the conformational transitions of the protein. This auxiliary binding site might indicate a potential regulatory role of heme in the FLVCR2 transport mechanisms. Our work resolves the contested substrate specificity of the FLVCRs, and sheds light on the process of maintaining cellular choline homeostasis at the molecular level.
Deviance detection describes an increase of neural response strength caused by a stimulus with a low probability of occurrence. This ubiquitous phenomenon has been reported for multiple species, from subthalamic areas to auditory cortex. While cortical deviance detection has been well characterised by a range of studies covering neural activity at population level (mismatch negativity, MMN) as well as at cellular level (stimulus-specific adaptation, SSA), subcortical deviance detection has been studied mainly on cellular level in the form of SSA. Here, we aim to bridge this gap by using noninvasively recorded auditory brainstem responses (ABRs) to investigate deviance detection at population level in the lower stations of the auditory system of a hearing specialist: the bat Carollia perspicillata. Our present approach uses behaviourally relevant vocalisation stimuli that are closer to the animals' natural soundscape than artificial stimuli used in previous studies that focussed on subcortical areas. We show that deviance detection in ABRs is significantly stronger for echolocation pulses than for social communication calls or artificial sounds, indicating that subthalamic deviance detection depends on the behavioural meaning of a stimulus. Additionally, complex physical sound features like frequency- and amplitude-modulation affected the strength of deviance detection in the ABR. In summary, our results suggest that at population level, the bat brain can detect different types of deviants already in the brainstem. This shows that subthalamic brain structures exhibit more advanced forms of deviance detection than previously known.
The small GTPases H, K, and NRAS are molecular switches that are indispensable for proper regulation of cellular proliferation and growth. Mutations in this family of proteins are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered novel variants of the Ras-binding domain (RBD) of the kinase CRAF. These variants bound with high affinity to the effector binding site of active Ras. Structural characterization showed how the newly identified mutations cooperate to enhance affinity to the effector binding site compared to RBDwt. The engineered RBD variants closely mimic the interaction mode of naturally occurring Ras effectors and as dominant negative affinity reagent block their activation. Experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling leading to a reduced growth and inductions of apoptosis. Using the optimized RBD variants, we stratified patient-derived colorectal cancer organoids according to Ras dependency, which showed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition.