A Microservice Infrastructure for Distributed Communities of Practice

Non-formal learning in Communities of Practice (CoPs) makes up a significant portion of today’s knowledge gain. However, only little technological support is tailored specifically towards CoPs and their particular strengths and challenges. Even worse, CoPs often do not possess the resources to host or even develop a software ecosystem to support their activities. In this paper, we describe a distributed, microservice-based Web infrastructure for non-formal learning in CoPs. It mitigates the need for central infrastructures, coordination or facilitation and takes into account the constant change of these communities. As a real use case, we implement an inquiry-based learning application on-top of our infrastructure. Our evaluation results indicate the usefulness of this learning application, which shows promise for future work in the domain of community-hosted, microservice-based Web infrastructures for learning outside of formal settings

A remark on an overdetermined problem in Riemannian Geometry

Let $(M,g)$ be a Riemannian manifold with a distinguished point $O$ and assume that the geodesic distance $d$ from $O$ is an isoparametric function. Let $\Omega\subset M$ be a bounded domain, with $O \in \Omega$, and consider the problem $\Delta_p u = -1$ in $\Omega$ with $u=0$ on $\partial \Omega$, where $\Delta_p$ is the $p$-Laplacian of $g$. We prove that if the normal derivative $\partial_{\nu}u$ of $u$ along the boundary of $\Omega$ is a function of $d$ satisfying suitable conditions, then $\Omega$ must be a geodesic ball. In particular, our result applies to open balls of $\mathbb{R}^n$ equipped with a rotationally symmetric metric of the form $g=dt^2+\rho^2(t)\,g_S$, where $g_S$ is the standard metric of the sphere.Comment: 8 pages. This paper has been written for possible publication in a special volume dedicated to the conference "Geometric Properties for Parabolic and Elliptic PDE's. 4th Italian-Japanese Workshop", organized in Palinuro in May 201

Osmotaxis in Escherichia coli through changes in motor speed

Bacterial motility, and in particular repulsion or attraction towards specific chemicals, has been a subject of investigation for over 100 years, resulting in detailed understanding of bacterial chemotaxis and the corresponding sensory network in many bacterial species. For Escherichia coli most of the current understanding comes from the experiments with low levels of chemotactically-active ligands. However, chemotactically-inactive chemical species at concentrations found in the human gastrointestinal tract produce significant changes in E. coli's osmotic pressure, and have been shown to lead to taxis. To understand how these nonspecific physical signals influence motility, we look at the response of individual bacterial flagellar motors under step-wise changes in external osmolarity. We combine these measurements with a population swimming assay under the same conditions. Unlike for chemotactic response, a long-term increase in swimming/motor speeds is observed, and in the motor rotational bias, both of which scale with the osmotic shock magnitude. We discuss how the speed changes we observe can lead to steady state bacterial accumulation.Comment: 24 pages, 11 figure

Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain Inhibitors†

Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99 % of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1 % of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone

Structure-Based Discovery of A2A Adenosine Receptor Ligands

The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A(2A) adenosine receptor, based on complementarity to its recently determined structure. The A(2A) adenosine receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 microM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A(2A) versus the related A(1) and A(3) subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we attempt to investigate quantitatively. Despite this bias, many of the most potent new ligands were novel, dissimilar from known ligands, providing new lead structures for modulation of this medically important target

Anti-emetic drugs in oncology: pharmacology and individualization by pharmacogenetics

Objective Nausea and vomiting are the most distressful side effects of cytotoxic drugs in cancer patients. Antiemetics are commonly used to reduce these side effects. However, the current antiemetic efficacy is about 70–80% in patients treated with highly-emetogenic cytotoxic drugs. One of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins which play a role in metabolism, transport and receptors related to antiemetic drugs. Aim of this review was to describe the pharmacology and pharmacogenetic concepts of of antiemetics in oncology. Method Pharmacogenetic and pharmacology studies of antiemetics in oncology published between January 1997 and February 2010 were searched in PubMed. Furthermore, related textbooks were also used for exploring the pharmacology of antiemetic drugs. The antiemetic drugs which were searched were the 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs), dopamine antagonists, corticosteroids, benzodiazepines, cannabinoids, antihistamines and neurokinin-1 antagonists. Result The 5-HT3RAs are widely used in highly emetogenic chemotherapy in combination with dexamethasone and a neurokinin-1 antagonist, especially in acute phase. However, the dopamine antagonists and benzodiazepines were found more appropriate for use in breakthrough and anticipatory symptoms or in preventing the delayed phase of chemotherapy induced nausea and vomiting. The use of cannabinoids and antihistamines need further investigation. Only six articles on pharmacogenetics of the 5-HT3RAs in highly emetogenic chemotherapy are published. Specifically, these studies investigated the association of the efficacy of 5-HT3RAs and variants in the multi drug resistance 1 (MDR1) gene, 5-HT3A,B and C receptor genes and CYP2D6 gene. The pharmacogenetic studies of the other antiemetics were not found in this review. Conclusion It is concluded that pharmacogenetic studies with antiemetics are sparse. It is too early to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice: confirmation of early findings is required

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia

Automated Docking Screens: A Feasibility Study

Molecular docking is themost practical approach to leverage protein structure for ligand discovery, but the technique retains important liabilities that make it challenging to deploy on a large scale. We have therefore created an expert system, DOCKBlaster, to investigate the feasibility of full automation. The method requires a PDB code, sometimes with a ligand structure, and from that alone can launch a full screen of large libraries. A critical feature is self-assessment, which estimates the anticipated reliability of the automated screening results using pose fidelity and enrichment. Against common benchmarks, DOCKBlaster recapitulates the crystal ligand pose within 2 A ̊ rmsd 50-60 % of the time; inferior to an expert, but respectrable. Half the time the ligand also ranked among the top 5 % of 100 physically matched decoys chosen on the fly. Further tests were undertaken culminating in a study of 7755 eligible PDB structures. In 1398 cases, the redocked ligand ranked in the top 5 % of 100 property-matched decoys while also posing within 2 A ̊ rmsd, suggesting that unsupervised prospective docking is viable. DOCK Blaster is available a

One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening†

The enzyme pteridine reductase 1 (PTR1) is a potential target for new compounds to treat human African trypanosomiasis. A virtual screening campaign for fragments inhibiting PTR1 was carried out. Two novel chemical series were identified containing aminobenzothiazole and aminobenzimidazole scaffolds, respectively. One of the hits (2-amino-6-chloro-benzimidazole) was subjected to crystal structure analysis and a high resolution crystal structure in complex with PTR1 was obtained, confirming the predicted binding mode. However, the crystal structures of two analogues (2-amino-benzimidazole and 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole) in complex with PTR1 revealed two alternative binding modes. In these complexes, previously unobserved protein movements and water-mediated protein-ligand contacts occurred, which prohibited a correct prediction of the binding modes. On the basis of the alternative bindingmode of 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole, derivatives were designed and selective PTR1 inhibitors with low nanomolar potency and favorable physicochemical properties were obtained