Two ways to solve ASEP

The purpose of this article is to describe the two approaches to compute exact formulas (which are amenable to asymptotic analysis) for the probability distribution of the current of particles past a given site in the asymmetric simple exclusion process (ASEP) with step initial data. The first approach is via a variant of the coordinate Bethe ansatz and was developed in work of Tracy and Widom in 2008-2009, while the second approach is via a rigorous version of the replica trick and was developed in work of Borodin, Sasamoto and the author in 2012.Comment: 10 pages, Chapter in "Topics in percolative and disordered systems

Ribosome recycling, diffusion, and mRNA loop formation in translational regulation

We explore and quantify the physical and biochemical mechanisms that may be relevant in the regulation of translation. After elongation and detachment from the 3' termination site of mRNA, parts of the ribosome machinery can diffuse back to the initiation site, especially if it is held nearby, enhancing overall translation rates. The elongation steps of the mRNA-bound ribosomes are modeled using exact and asymptotic results of the totally asymmetric exclusion process (TASEP).Since the ribosome injection rates of the TASEP depend on the local concentrations at the initiation site, a source of ribosomes emanating from the termination end can feed back to the initiation site, leading to a self-consistent set of equations for the steady-state ribosome throughput. Additional mRNA binding factors can also promote loop formation, or cyclization, bringing the initiation and termination sites into close proximity. The probability distribution of the distance between the initiation and termination sites is described using simple noninteracting polymer models. We find that the initiation, or initial ribosome adsorption binding required for maximal throughput can vary dramatically depending on certain values of the bulk ribosome concentration and diffusion constant. If cooperative interactions among the loop-promoting proteins and the initiation/termination sites are considered, the throughput can be further regulated in a nonmonotonic manner. Potential experiments to test the hypothesized physical mechanisms are discussed.Comment: 21 pp, 11 .eps figs, realigned figures and magin

An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects. These issues might be addressed by the additional use of host-directed antivirals (HDAs). As a strong input from long-term experiences with cancer therapies, host protein kinases may serve as HDA targets of mechanistically new antiviral drugs. The study demonstrates such a novel antiviral strategy by targeting the major virus-supportive host kinase CDK7. Importantly, this strategy focuses on highly selective, 3D structure-derived CDK7 inhibitors carrying a warhead moiety that mediates covalent target binding. In summary, the main experimental findings of this study are as follows: (1) the in vitro verification of CDK7 inhibition and selectivity that confirms the warhead covalent-binding principle (by CDK-specific kinase assays), (2) the highly pronounced antiviral efficacies of the hit compounds (in cultured cell-based infection models) with half-maximal effective concentrations that reach down to picomolar levels, (3) a particularly strong potency of compounds against strains and reporter-expressing recombinants of HCMV (using infection assays in primary human fibroblasts), (4) additional activity against further herpesviruses such as animal CMVs and VZV, (5) unique mechanistic properties that include an immediate block of HCMV replication directed early (determined by Western blot detection of viral marker proteins), (6) a substantial drug synergism in combination with MBV (measured by a Loewe additivity fixed-dose assay), and (7) a strong sensitivity of clinically relevant HCMV mutants carrying MBV or ganciclovir resistance markers. Combined, the data highlight the huge developmental potential of this host-directed antiviral targeting concept utilizing covalently binding CDK7 inhibitors

A search for circumstellar dust disks with ADONIS

We present results of a coronographic imaging search for circumstellar dust disks with the Adaptive Optics Near Infrared System (ADONIS) at the ESO 3.6m telescope in La Silla (Chile). 22 candidate stars, known to be orbited by a planet or to show infrared excess radiation, were examined for circumstellar material. In the PSF-subtracted images no clear disk was found. We further determine the detection sensitivities and outline how remaining atmospheric fluctuations still can hamper adaptive optics observations.Comment: To appear in A&A, in pres

The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism

Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting

Partnerorientierung zwischen Realität und Imagination: Anmerkungen zu einem zentralen Konzept der Dialogtheorie

This paper attempts a critique of the notion of 'dialogue' in dialogue theory as espoused by Linell, Markova, and others building on Bakhtin’s writings. According to them, human communication, culture, language, and even cognition are dialogical in nature. This implies that these domains work by principles of other-orientation and interaction. In our paper, we reject accepting other-orientation as an a priori condition of every semiotic action. Instead, we claim that in order to be an empirically useful concept for the social sciences, it must be shown if and how observable action is other-oriented. This leads us to the following questions: how can we methodically account for other-orientation of semiotic action? Does other-orientation always imply interaction? Is every human expression oriented towards others? How does the other, as s/he is represented in semiotic action, relate to the properties which the other can be seen to exhibit as indexed by their observable behavior? We study these questions by asking how the orientation towards others becomes evident in different forms of communication. For this concern, we introduce ‘recipient design’, ‘positioning’ and ‘intersubjectivity’ as concepts which allow us to inquire how semiotic action both takes the other into account and, reflexively, shapes him/her as an addressee having certain properties. We then specifically focus on actions and situations in which other-orientation is particularly problematic, such as interactions with children, animals, machines, or communication with unknown recipients via mass media. These borderline cases are scrutinized in order to delineate both limits and constitutive properties of other-orientation. We show that there are varieties of meaningful actions which do not exhibit an orientation towards the other, which do not rest on (the possibility of) interaction with the other or which even disregard what their producer can be taken to know about the other. Available knowledge about the other may be ignored in order to reach interactional goals, e. g. in strategical interactions or for concerns of socialization. If semiotic action is otherorientated, its design depends on how the other is available to and matters for their producer. Other-orientation may build on shared biographical experiences with the other, knowledge about the other as an individual and close attention to their situated conduct. However, other-orientation may also rest on (stereo-)typification with respect to institutional roles or group membership. In any case, others as they are represented in semiotic action can never be just others-as-such, but only othersas-perceived-by-the-actor. We conclude that the strong emphasis which dialogue theories put on otherorientation obscures that other-orientation is neither universal in semiotic action, that it must be distinguished from an interactive relationship, and that the ways in which the other figures in semiotic actions is not homogeneous in any of its most general properties. Instead, there is a huge variation in the ways in which the other can be taken into account. Therefore close scrutiny of how the other precisely figures in a certain kind of semiotic action is needed in order to lend the concept of ‘other-orientation’ empirical substance and a definite sense

24-h sheltering behaviour of individually kept horses during Swedish summer weather

Provision of shelter for horses kept on summer pasture is rarely considered in welfare guidelines, perhaps because the benefits of shelter in warm conditions are poorly documented scientifically. For cattle, shade is a valued resource during summer and can mitigate the adverse effects of warm weather on well-being and performance. We found in a previous study that horses utilized shelters frequently in summer. A shelter with a roof and closed on three sides (shelter A) was preferred and can reduce insect pressure whereas a shelter with roof and open on three sides was not utilized. However, shelter A restricts the all-round view of a horse, which may be important for horses as flight animals. Therefore, we studied whether a shelter with roof, where only the upper half of the rear wall was closed (shelter B), would be utilized while maintaining insect protection properties and satisfying the horses’ sense for security. A third shelter was offered with walls but no roof (shelter C) to evaluate whether the roof itself is an important feature from the horse’s perspective. Eight Warmblood horses were tested each for 2 days, kept individually for 24 h in two paddocks with access to shelters A and B, or shelters A and C, respectively. Shelter use was recorded continuously during the night (1800–2400 h, 0200–0600 h) and the following day (0900–1600 h), and insect defensive behaviour (e.g., tail swish) in instantaneous scan samples at 5-min intervals during daytime

Crowdsourcing hypothesis tests: Making transparent how design choices shape research results

To what extent are research results influenced by subjective decisions that scientists make as they design studies? Fifteen research teams independently designed studies to answer fiveoriginal research questions related to moral judgments, negotiations, and implicit cognition. Participants from two separate large samples (total N > 15,000) were then randomly assigned to complete one version of each study. Effect sizes varied dramatically across different sets of materials designed to test the same hypothesis: materials from different teams renderedstatistically significant effects in opposite directions for four out of five hypotheses, with the narrowest range in estimates being d = -0.37 to +0.26. Meta-analysis and a Bayesian perspective on the results revealed overall support for two hypotheses, and a lack of support for three hypotheses. Overall, practically none of the variability in effect sizes was attributable to the skill of the research team in designing materials, while considerable variability was attributable to the hypothesis being tested. In a forecasting survey, predictions of other scientists were significantly correlated with study results, both across and within hypotheses. Crowdsourced testing of research hypotheses helps reveal the true consistency of empirical support for a scientific claim.</div