Achievement of specificational information usage with true and false feedback in learning a visual relative-mass discrimination task.

Participants' usage of informational variables in learning visual relative-mass discrimination in collisions was tracked by means of PROBIT correlations. Four groups received feedback that was true or accorded with either of three nonspecificational cue variables. A majority in each group adopted the feedback, but several participants defied the false feedback. Unlike in previous research, the fit to data of the relative-mass invariant could not be bettered by post hoc linear combinations of the cues. Discriminability was lower in the use of the invariant. Analytic complexity was rejected as an explanation for discriminability differences. A "smart mechanism" for pickup of the relative-mass invariant was developed as an extension of G. Johansson's (1950/1994) vector model. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Loss of heterozygosity of the von Hippel Lindau gene locus in polypoid dysplasia but not flat dysplasia in ulcerative colitis or sporadic adenomas

Carcinoma in ulcerative colitis (UC) develops from dysplastic precursor lesions, which include flat dysplasia (FD) and polypoid dysplasias (PD). PD may present as single or multiple polypoid structures or as plaque-like lesions that, independent of histological grade, are an indication for colectomy. PDs are histologically similar to adenomas and may not be readily distinguished by light microscopy. It is not known whether FD and PD are different entities, or whether they represent etiologically similar lesions with different morphological expression. We microdissected 25 cases of UC with PD and 19 samples of FD with surrounding chronic colitis (CC) in UC. Loss of heterozygosity (LOH) at the von Hippel Lindau (vHL) gene locus and the putative tumor suppressor genes APC, INK4A (9p16), and p53 was studied. LOH of the vHL gene, INK4A (9p16), and APC was also studied in 11 sporadic adenomas of the colon. LOH at the vHL locus was present in 50% of the samples of PD and in 12% of the samples of FD. LOH was seen in CC close to PD and FD in 26% and 12% of cases, respectively. No adenoma showed LOH of the vHL gene markers studied. LOH in p53 was seen in PD in 16% cases and in FD in 42% cases and in CC close to PD and FD in 0% and 14% cases, respectively. LOH patterns between PD and FD of the markers for APC and 9p16 were not different. LOH in APC was seen in two of five cases of adenoma. We conclude that PD and FD share genetic alterations in APC and 9p16 genes. More frequent involvement of the VHL gene in PD and surrounding CC and involvement of p53 in HGD and CC in FD may represent genetic differences between the development of PD and FD and may be the cause of the different morphology. The infrequency of LOH at the vHL locus in adenomas versus PD may serve as a discriminator between adenomas and PD in diagnostically problematic cases.     

Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.     

Discovery–Versus Hypothesis–Driven Detection of Protein–Protein Interactions and Complexes

Protein complexes are the main functional modules in the cell that coordinate and perform the vast majority of molecular functions. The main approaches to identify and quantify the interactome to date are based on mass spectrometry (MS). Here I summarize the benefits and limitations of different MS-based interactome screens, with a focus on untargeted interactome acquisition, such as co-fractionation MS. Specific emphasis is given to the discussion of discovery- versus hypothesis-driven data analysis concepts and their applicability to large, proteome-wide interactome screens. Hypothesis-driven analysis approaches, i.e., complex- or network-centric, are highlighted as promising strategies for comparative studies. While these approaches require prior information from public databases, also reviewed herein, the available wealth of interactomic data continuously increases, thereby providing more exhaustive information for future studies. Finally, guidance on the selection of interactome acquisition and analysis methods is provided to aid the reader in the design of protein-protein interaction studies.     

A system framework for gamified Cost Engineering

This study develops a system framework and an enterprise IT solution for integrating gamification elements to efficiently implement and continuously perform Cost Engineering. Cost Engineering is a systematic approach to manage knowledge and competencies regarding costs reduction measures throughout the life cycle of products and is technology, resource and time intensive. Gamification as a non-monetary multidimensional incentive system holds great potential to implement and establish Cost Engineering in a novel and less resource demanding manner and stipulate knowledge sharing and dissemination. Building on a review of the relevant literature we conducted 20 interviews with experts from eight companies of the German and Austrian high-tech manufacturing industry to examine the system requirements from an organizational perspective. Analyzing the interviews, we found that companies need a flexible platform where the game elements help to align management objectives with concrete tasks, meet legislative regulations and have different evaluation methods. Our proposed system framework combines the organizational and IT requirements with gamification elements to efficiently steer Cost Engineering methods and best manage knowledge and competencies.     

Graphical histories for visualization: supporting analysis, communication, and evaluation

Interactive history tools, ranging from basic undo and redo to branching timelines of user actions, facilitate iterative forms of interaction. In this paper, we investigate the design of history mechanisms for information visualization. We present a design space analysis of both architectural and interface issues, identifying design decisions and associated trade-offs. Based on this analysis, we contribute a design study of graphical history tools for Tableau, a database visualization system. These tools record and visualize interaction histories, support data analysis and communication of findings, and contribute novel mechanisms for presenting, managing, and exporting histories. Furthermore, we have analyzed aggregated collections of history sessions to evaluate Tableau usage. We describe additional tools for analyzing users’ history logs and how they have been applied to study usage patterns in Tableau.     

Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH‐102

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH‐101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg^?1) of the closely related analogue UCPH‐102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH‐102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH‐102 (10 μm ) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH‐102 (20 mg kg^?1) did not induce acute effects or any visible changes in behavior.     

Size-Dependent Cellular Uptake of RGD Peptides

Monomeric RGD peptides show unspecific fluid-phase uptake in cells, whereas multimeric RGD peptides are thought to be internalized by integrin-mediated endocytosis. However, a potential correlation between uptake mechanism and molecular mass has been neglected so far. A dual derivatization of peptide c(RGDw(7Br)K) was performed to investigate this. A fluorescent probe was installed by chemoselective Suzuki–Miyaura cross-coupling of the 7-bromotryptophan and a poly(ethylene glycol) (PEG) linker was attached to the lysine residue. Flow cytometry and live cell imaging confirmed unspecific uptake of the small, non-PEGylated peptide, whereas the PEG₅₀₀₀ peptide conjugate unveiled a selective internalization by M21 cells overexpressing α_vβ₃ and no uptake in α_v-deficient M21L cells.     

Loss of heterozygosity and microsatellite instability in de novo versus ex-adenoma carcinomas of the colorectum

Small adenocarcinomas of the colorectum showing no evidence of origin from an adenoma have been called de novo carcinomas, a name that implies an origin via a different molecular genetic mechanism than the usual colorectal carcinoma which develops from an adenoma. Using microsatellite analysis, 35 early (pT1) de novo and 36 pT1 ex-adenoma carcinomas were compared using 8 microsatellite loci at 6 different chromosomal loci (1p, 2p, 8p, 5q, 17p, and 18q) known or hypothesized to be important for colorectal carcinogenesis. The rate of loss of heterozygosity (LOH) at the 17p locus (near the p53 gene) was significantly higher in the de novo than in the ex-adenoma group (73 vs. 37%, P = 0.004). The rates of LOH at the other loci (including the APC and DCC genes) and the rate of MSI were not significantly different in the two groups. These results indicate that de novo carcinomas of the colorectum develop via a similar carcinogenetic pathway as conventional ex-adenoma carcinomas; however, their higher rate of LOH at 17p is evidence for a biologically more advanced lesion with more frequent p53 mutations, consistent with clinicopathological data indicating that de novo carcinomas are more aggressive than ex-adenoma carcinomas.     

Chromium-doped forsterite: dispersion measurement with white-light interferometry

Using a Michelson white-light interferometer, we measure the group-delay dispersion and third-order dispersion coefficients, d2(phi)/d(omega)2 and d3(phi)/d(omega)3, of chromium-doped forsterite (Cr:Mg2SiO4) over wavelengths of 1050-1600 nm for light polarized along both the c and b crystal axes. In this interval, the second-order dispersion for the c axis ranges from 35 fs2/mm to -14 fs2/mm, and the third-order dispersion ranges from 36 fs3/mm to 142 fs3/mm. For the b axis the second-order dispersion ranges from 35 fs2/mm to -15 fs2/mm and the third-order from 73 fs3/mm to 185 fs3/mm. Our data are relevant for the development of optimized dispersion compensation tools for Cr:Mg2SiO4 femtosecond lasers. These measurements help to clarify previously published results and show some significant discrepancies that existed, especially in the third-order dispersion. Our results should furthermore be useful to build up an analytic expression for the index of refraction of chromium forsterite.