Optimised planning and scheduling of grid resources

This article will present the concept and implementation of a resource management system (RMS). The central component of the RMS is the resource broker GORBA that plans resource allocation by a combination of heuristic processes and evolutionary algorithms. For resource planning, schedules are generated, which distribute the grid jobs to the grid resources in a defined time window. A test environment with extensive visualisation options was developed for GORBA, which will be presented in detail. Using this test environment, benchmark runs were carried out, which are needed to evaluate and further develop GORBA. Automated resource planning and the graphic visualisation options facilitate the usability of a grid environment

Optimised planning and scheduling of grid resources

This article will present the concept and implementation of a resource management system (RMS). The central component of the RMS is the resource broker GORBA that plans resource allocation by a combination of heuristic processes and evolutionary algorithms. For resource planning, schedules are generated, which distribute the grid jobs to the grid resources in a defined time window. A test environment with extensive visualisation options was developed for GORBA, which will be presented in detail. Using this test environment, benchmark runs were carried out, which are needed to evaluate and further develop GORBA. Automated resource planning and the graphic visualisation options facilitate the usability of a grid environment

On the effects of roughness on the nonlinear dynamics of a bolted joint: a multiscale analysis

Accurate prediction of the vibration response of friction joints is of great importance when estimating both the performance and the life of build-up structures. The contact conditions at the joint interface, including local normal load distribution and contact stiffness, play a critical role in the nonlinear dynamic response. These parameters strongly depend on the mating surfaces, where the surface roughness is well known to have a significant impact on the contact conditions in the static case. In contrast, its effects on the global and local nonlinear dynamic response of a build-up structure is not as well understood due to the complexity of the involved mechanisms. To obtain a better understanding of the dependence of the nonlinear dynamic response on surface roughness, a newly proposed multiscale approach has been developed. It links the surface roughness to the contact pressure and contact stiffness, and in combination with a multiharmonic balance solver, allows to compute the nonlinear dynamic response for different interface roughness. An application of the technique to a single bolted lap joint highlighted a strong impact of larger roughness values on the pressure distribution and local contact stiffness and in turn on the nonlinear dynamic response

On the classification of Kahler-Ricci solitons on Gorenstein del Pezzo surfaces

We give a classification of all pairs (X,v) of Gorenstein del Pezzo surfaces X and vector fields v which are K-stable in the sense of Berman-Nystrom and therefore are expected to admit a Kahler-Ricci solition. Moreover, we provide some new examples of Fano threefolds admitting a Kahler-Ricci soliton.Comment: 21 pages, ancillary files containing calculations in SageMath; minor correction

Predicting protein targets for drug-like compounds using transcriptomics

An expanded chemical space is essential for improved identification of small molecules for emerging therapeutic targets. However, the identification of targets for novel compounds is biased towards the synthesis of known scaffolds that bind familiar protein families, limiting the exploration of chemical space. To change this paradigm, we validated a new pipeline that identifies small molecule-protein interactions and works even for compounds lacking similarity to known drugs. Based on differential mRNA profiles in multiple cell types exposed to drugs and in which gene knockdowns (KD) were conducted, we showed that drugs induce gene regulatory networks that correlate with those produced after silencing protein-coding genes. Next, we applied supervised machine learning to exploit drug-KD signature correlations and enriched our predictions using an orthogonal structure-based screen. As a proof-of-principle for this regimen, top-10/top-100 target prediction accuracies of 26% and 41%, respectively, were achieved on a validation of set 152 FDA-approved drugs and 3104 potential targets. We then predicted targets for 1680 compounds and validated chemical interactors with four targets that have proven difficult to chemically modulate, including non-covalent inhibitors of HRAS and KRAS. Importantly, drug-target interactions manifest as gene expression correlations between drug treatment and both target gene KD and KD of genes that act up- or down-stream of the target, even for relatively weak binders. These correlations provide new insights on the cellular response of disrupting protein interactions and highlight the complex genetic phenotypes of drug treatment. With further refinement, our pipeline may accelerate the identification and development of novel chemical classes by screening compound-target interactions.Fil: Pabon, Nicolas. University of Pittsburgh; Estados UnidosFil: Xia, Yan. University of Carnegie Mellon; Estados UnidosFil: Estabrooks, Samuel K.. University of Pittsburgh; Estados UnidosFil: Ye, Zhaofeng. Tsinghua University; ChinaFil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; AlemaniaFil: Süß, Evelyn. Goethe Universitat Frankfurt; AlemaniaFil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Goethe Universitat Frankfurt; AlemaniaFil: Assimon, Victoria A.. University of California; Estados UnidosFil: Gestwicki, Jason E.. University of California; Estados UnidosFil: Brodsky, Jeffrey L.. University of Pittsburgh; Estados UnidosFil: Camacho, Carlos. University of Pittsburgh; Estados UnidosFil: Bar Joseph, Ziv. University of Carnegie Mellon; Estados Unido

Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds

The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins and modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells. Here, we employed chemical biology methods to investigate the allosteric communication between the PBD and the catalytic domain of Plk1. We identified small compounds that bind to the catalytic domain and inhibit or enhance the interaction of Plk1 with the phosphorylated peptide PoloBoxtide in vitro. In cells, two new allosteric Plk1 inhibitors affected the proliferation of cancer cells in culture and the cell cycle but had distinct phenotypic effects on spindle formation. Both compounds inhibited Plk1 signaling, indicating that they specifically act on Plk1 in cultured cells.Fil: Raab, Monika. Goethe Universitat Frankfurt; AlemaniaFil: Sanhaji, Mourad. Goethe Universitat Frankfurt; AlemaniaFil: Pietsch, Larissa. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; AlemaniaFil: Béquignon, Isabelle. Goethe Universitat Frankfurt; AlemaniaFil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; AlemaniaFil: Süß, Evelyn. Goethe Universitat Frankfurt; AlemaniaFil: Gande, Santosh L.. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; AlemaniaFil: Caspar, Birgit. Goethe Universitat Frankfurt; AlemaniaFil: Kudlinzki, Denis. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; AlemaniaFil: Saxena, Krishna. Goethe Universitat Frankfurt; AlemaniaFil: Sreeramulu, Sridhar. Goethe Universitat Frankfurt; AlemaniaFil: Schwalbe, Harald. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; AlemaniaFil: Strebhardt, Klaus. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; AlemaniaFil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentin

Web-based occupational stress prevention in German micro- and small-sized enterprises – process evaluation results of an implementation study

Background: Structural and behavioral interventions to manage work-related stress are effective in employees. Nonetheless, they have been implemented insufficiently, particularly in micro- and small-sized enterprises (MSE). Main barriers include a lack of knowledge and limited resources, which could potentially be overcome with simplified web-based alternatives for occupational stress prevention. However, there is a lack of implementation research about web-based prevention in realistic settings of MSE.Objective: The aim of this study is to evaluate the implementation process and success of an integrated web-based platform for occupational stress prevention (“System P”) and to identify potential barriers for its uptake and use in MSE in Germany. Methods: This study with a mixed-methods approach investigates eight process-related outcomes in a quantitative part I (adoption, reach, penetration, fidelity/dose, costs, acceptability) and a qualitative part II (acceptability, appropriateness and feasibility). Part I has a pre-post design with two measurements (6 months apart) with 98 individual participants and part II consists of 12 semi-structured interviews with managers and intercorporate stakeholders.Results: Part I revealed shortcomings in the implementation process. Adoption/Reach: Despite extensive marketing efforts, less than 1% of the contacted MSE responded to the offer of System P. A total of 40 MSE registered, 24 of which, characterized by good psychosocial safety climate, adopted System P. Penetration: Within these 24 MSE, 15% of the employees used the system. Fidelity/Dose: 11 MSE started a psychosocial risk-assessment (PRA), and no MSE finished it. The stress-management training (SMT) was started by 25 users and completed by 8. Costs: The use of System P was free of charge, but the time required to engage with was an indirect cost. Part II added insights on the perception of the web-based intervention: Acceptance of System P by users and stakeholders was good and it was assessed as appropriate for MSE. Results for feasibility were mixed. Conclusions: Although System P was generally perceived as useful and appropriate, only a small number of contacted MSE implemented it as intended. Prior experience and sensitivity for occupational (stress) prevention were mentioned as key facilitators, while (perceived) indirect costs were a key barrier. Enabling MSE to independently manage stress prevention online did not result in successful implementation. Increasing external support could be a solution. ⁺ Full project name: “PragmatiKK – Pragmatische Lösungen für die Implementation von Maßnahmen zur Stressprävention in Kleinst- und Kleinbetrieben” (= Pragmatic solutions for the implementation of stress prevention interventions in micro and small-sized enterprises). Trial registration: German Register of Clinical Studies (DRKS) DRKS00026154, date of registration 2021-09-16.</p

Experimental signatures of the mixed axial-gravitational anomaly in the Weyl semimetal NbP

Weyl semimetals are materials where electrons behave effectively as a kind of massless relativistic particles known asWeyl fermions. These particles occur in two flavours, or chiralities, and are subject to quantum anomalies, the breaking of a conservation law by quantum fluctuations. For instance, the number of Weyl fermions of each chirality is not independently conserved in parallel electric and magnetic field, a phenomenon known as the chiral anomaly. In addition, an underlying curved spacetime provides a distinct contribution to a chiral imbalance, an effect known as the mixed axial-gravitational anomaly, which remains experimentally elusive. However, the presence of a mixed gauge-gravitational anomaly has recently been tied to thermoelectrical transport in a magnetic field, even in flat spacetime, opening the door to experimentally probe such type of anomalies in Weyl semimetals. Using a temperature gradient, we experimentally observe a positive longitudinal magnetothermoelectric conductance (PMTC) in the Weyl semimetal NbP for collinear temperature gradients and magnetic fields (DT || B) that vanishes in the ultra quantum limit. This observation is consistent with the presence of a mixed axial-gravitational anomaly. Our work provides clear experimental evidence for the existence of a mixed axial-gravitational anomaly of Weyl fermions, an outstanding theoretical concept that has so far eluded experimental detection

Does working memory training have to be adaptive?

This study tested the common assumption that, to be most effective, working memory (WM) training should be adaptive (i.e., task difficulty is adjusted to individual performance). Indirect evidence for this assumption stems from studies comparing adaptive training to a condition in which tasks are practiced on the easiest level of difficulty only [cf. Klingberg (Trends Cogn Sci 14:317-324, 2010)], thereby, however, confounding adaptivity and exposure to varying task difficulty. For a more direct test of this hypothesis, we randomly assigned 130 young adults to one of the three WM training procedures (adaptive, randomized, or self-selected change in training task difficulty) or to an active control group. Despite large performance increases in the trained WM tasks, we observed neither transfer to untrained structurally dissimilar WM tasks nor far transfer to reasoning. Surprisingly, neither training nor transfer effects were modulated by training procedure, indicating that exposure to varying levels of task difficulty is sufficient for inducing training gains