Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets

Unbiased morphological profiling of bioactivity, for example, in the cell painting assay (CPA), enables the identification of a small molecule's mode of action based on its similarity to the bioactivity of reference compounds, irrespective of the biological target or chemical similarity. This is particularly important for small molecules with nonprotein targets as these are rather difficult to identify with widely employed target-identification methods. We employed morphological profiling using the CPA to identify compounds that are biosimilar to the iron chelator deferoxamine. Structurally different compounds with different annotated cellular targets provoked a shared physiological response, thereby defining a cluster based on their morphological fingerprints. This cluster is based on a shared mode of action and not on a shared target, that is, cell-cycle modulation in the S or G2 phase. Hierarchical clustering of morphological fingerprints revealed subclusters that are based on the mechanism of action and could be used to predict target-related bioactivity.     

Bottom-gated epitaxial graphene

High-quality epitaxial graphene on silicon carbide (SiC) is today available in wafer size. Similar to exfoliated graphene, its charge carriers are governed by the Dirac-Weyl Hamiltonian and it shows excellent mobilities. For many experiments with graphene, in particular for surface science, a bottom gate is desirable. Commonly, exfoliated graphene flakes are placed on an oxidized silicon wafer that readily provides a bottom gate. However, this cannot be applied to epitaxial graphene as the SiC provides the source material out of which graphene grows. Here, we present a reliable scheme for the fabrication of bottom-gated epitaxial graphene devices, which is based on nitrogen (N) implantation into a SiC wafer and subsequent graphene growth. We demonstrate working devices in a broad temperature range from 6 to 300 K. Two gating regimes can be addressed, which opens a wide engineering space for tailored devices by controlling the doping of the gate structure.     

Wärmerückgewinnung an Holzspänetrocknern bei gleichzeitiger Verminderung der im Abgas enthaltenen Verunreinigungen

Tests with recuperating heat exchanging systems using chip dryer exhaust heat heave hitherto rarely been carried out in the particleboard industry. Dust, condensed terpines and resins contained in the exhaust gas clog any type of heat exchanger in a matter of hours, regardless of whether a ribbed tube bundle or crossflow heat exchanger is used. Removal of these deposits previously involved great effort. This paper describes a direct process for maximum energy utilization in chip dryers with coneurrent reduction of impurities in the exhaust gas. With the aid of a pilot recupertafor the data required to construct a large-scale recuperating system were derived from an industrial chip dryer. Rescarch to date has been promising. It is now possible to predict how large-scale plant would function.     

Seeing Versus Doing: Two Modes of Accessing Causal Knowledge.

The ability to derive predictions for the outcomes of potential actions from observational data is one of the hallmarks of true causal reasoning. We present four learning experiments with deterministic and probabilistic data showing that people indeed make different predictions from causal models, whose parameters were learned in a purely observational learning phase, depending on whether learners believe that an event within the model has been merely observed ("seeing") or was actively manipulated ("doing"). The predictions reflect sensitivity both to the structure of the causal models and to the size of their parameters. This competency is remarkable because the predictions for potential interventions were very different from the patterns that had actually been observed. Whereas associative and probabilistic theories fail, recent developments of causal Bayes net theories provide tools for modeling this competency. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparing Instance Generation Methods for Automated Reasoning

The clause-linking technique of Lee and Plaisted proves the unsatisfiability of a set of first-order clauses by generating a sufficiently large set of instances of these clauses that can be shown to be propositionally unsatisfiable. In recent years, this approach has been refined in several directions, leading to both tableau-based methods, such as the disconnection tableau calculus, and saturation-based methods, such as primal partial instantiation and resolution-based instance generation. We investigate the relationship between these calculi and answer the question to what extent refutation or consistency proofs in one calculus can be simulated in another one. This work was partly supported by the German Research Council (DFG) as part of the Transregional Collaborative Research Center “Automatic Verification and Analysis of Complex Systems” (SFB/TR 14 AVACS). See for more information.     

The pharmacokinetic characteristics of glycolated humanized anti-Tac Fabs are determined by their isoelectric points

To evaluate a method for preventing the nephrotoxicity caused by the high renal accumulation of radiolabeled or toxin-conjugated small immunoproteins used for cancer therapy, we conjugated humanized anti-Tac Fab fragments with various numbers of glycolate molecules [glycolated Fab fragments (glyco-Fabs)] and separated the conjugates by means of ion-exchange columns into three fractions, depending on their isoelectric points (pIs). We evaluated the biodistribution, pharmacokinetics, and catabolism in normal nude mice of nonglycolated Fab (pI > or = 9.3) and three different preparations of glyco-Fab, including strongly anionic glyco-Fab (sa-glyco-Fab: pI < or = 4.5), mildly anionic glyco-Fab (pI = 4.5-7), and mildly cationic glyco-Fab (pI = 7-9.3). In addition, the biodistributions of 125I-labeled sa-glyco-Fab and 131I-labeled nonglycolated Fab were evaluated in normal nude mice coinjected with 50 mg of L-lysine and/or 1 microg of furosemide and in a control group without coinjection. We then evaluated the serial biodistribution of 125I-labeled sa-glyco-Fab (4 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg) in Tac antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice with s.c. tumor xenografts derived from Tac antigen-positive ATAC4 cells and receptor-negative A431 cells. These animals were coinjected with 30 mg of lysine i.v. and 30 mg of lysine i.p. 15 min after the radiolabeled Fab injection. To evaluate the biodistribution data and study scintigraphic imaging, we performed serial scintigraphy on normal and tumor-bearing mice with all four 131I-labeled preparations. 125I-labeled mildly cationic glyco-Fab and 131I-labeled nonglycolated Fab had similar distributions, except in the kidney. However, both 125I-labeled anionic glyco-Fab preparations showed significantly different distributions from both cationic Fabs in the blood, liver, lung, and spleen. Renal accumulation of all four radiolabeled Fab preparations increased significantly as the pI increased (P < 0.01). In addition, the intact fraction of Fab excreted into urine increased as pI decreased. Therefore, the glomerular filtration depended on whether the charge on the Fab was positive or negative. The proportion of Fab reabsorbed by the proximal tubules increased as pI increased. 125I-labeled sa-glyco-Fab and 125I-labeled mildly anionic glyco-Fab showed a similar distribution in the blood and all organs except the kidney. Lysine led to an additional blocking effect on proximal tubular uptake of both sa-glyco-Fab and nonglycolated Fab. Addition of furosemide yielded only a small effect when used with lysine. With lysine, the sa-glyco-Fab:nonglycolated Fab estimated integral radioactivity ratios were 4.7 and 0.7 in the ATAC4 tumor and in the kidney, respectively. The use of anionic fragments, which may be used in conjunction with lysine, represents a promising approach that may help decrease the renal toxicity of other small fragments, the molecular weights of which range from Mr 40,000 to 70,000, and, thereby, allow higher doses of radiation to the tumor.