Towards validation of a new computerised test of goal neglect: preliminary evidence from clinical and neuroimaging pilot studies

Objective: Goal neglect is a significant problem following brain injury, and is a target for rehabilitation. It is not yet known how neural activation might change to reflect rehabilitation gains. We developed a computerised multiple elements test (CMET), suitable for use in neuroimaging paradigms. Design: Pilot correlational study and event-related fMRI study. Methods: In Study 1, 18 adults with acquired brain injury were assessed using the CMET, other tests of goal neglect (Hotel Test; Modified Six Elements Test) and tests of reasoning. In Study 2, 12 healthy adults underwent fMRI, during which the CMET was administered under two conditions: self-generated switching and experimenter-prompted switching. Results: Among the clinical sample, CMET performance was positively correlated with both the Hotel Test (r = 0.675, p = 0.003) and the Modified Six Elements Test (r = 0.568, p = 0.014), but not with other clinical or demographic measures. In the healthy sample, fMRI demonstrated significant activation in rostro-lateral prefrontal cortex in the self-generated condition compared with the prompted condition (peak 40, 44, 4; ZE = 4.25, p(FWEcorr) = 0.026). Conclusions: These pilot studies provide preliminary evidence towards the validation of the CMET as a measure of goal neglect. Future studies will aim to further establish its psychometric properties, and determine optimum pre- and post-rehabilitation fMRI paradigms

Defining Success: Examining What it Means to be Good in Forensics

For decades college students have been competing in forensic activity (forensics), spending countless hours researching, writing, and performing speeches. Forensic scholars have never created an overarching definition of what it means to be successful in forensics. A survey was created and sent out on the individual events listserv, asking competitors and coaches to define success. Analysis reveals both competitors and coaches believe success in forensics is a combination of competitive achievement, building communication skills, and personal growth

The research buyer\u27s perspective of market research effectiveness

This study examines the views of research buyers about the efficacy of market research used within their firms. A sample of research buyers from Australia's top 1000 companies was asked to evaluate the research outcomes of their most recent market research project in terms of their overall business strategy. Specialist market research buyers (insights managers) believed their commissioned research was very effective. This was in contrast to research buyers in generalist roles who did not believe in the effectiveness of the research outcomes to the same extent. The overarchlng strategic direction adopted by the buyer's firm did not make a difference to the type of research conducted (,action orientated' vs. 'knowledge enhancing'). However, entrepreneurial firms were more likely to rate their research as effective and to have dedicated research buyers generating insights into their markets. The results of this study are inconsistent with earlier studies and indicate that the market research function within Australian firms stili plays an ambiguous role

Awash in E-Journal Data: What It Is, Where It Is, and What Can Be Done with It (Is It “Too Much” or “Not Enough?”)

Libraries have been collecting e-journal data for some time. With the variety of data sources available, it is often difficult to determine their utility. This session explores the Penn State experience with navigating a number of data sources and their limitations and usefulness to advance library management objectives, as well as other institutional objectives. We will look at the COUNTER-compliant JR1 and JR1a data sets and standards (how they are derived and what issues there are with the data), as well as publishing and citation data (e.g., Web of Science) that shows faculty activity in publishing and their participation in editorial activities. What can we learn from these data? The objective of the session is to stimulate ideas and discussion for applications of the data we collect, ways of manipulating data sets, and including this process in overall analysis workflows

Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites

The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.Work in the DJH laboratory is supported by the Medical Research Council under grant ML/L007266/1. All calculations were performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/) provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England, and were funded by the EPSRC under grants EP/F032773/1 and EP/J017639/1

Geographic Variation in Informed Consent Law: Two Standards for Disclosure of Treatment Risks

We analyzed 714 jury verdicts in informed consent cases tried in 25 states in 1985–2002 to determine whether the applicable standard of care (“patient” vs. “professional” standard) affected the outcome. Verdicts for plaintiffs were significantly more frequent in states with a patient standard than in states with a professional standard (27 percent vs. 17 percent, P = 0.02). This difference in outcomes did not hold for other types of medical malpractice litigation (36 percent vs. 37 percent, P = 0.8). The multivariate odds of a plaintiff’s verdict were more than twice as high in states with a patient standard than in states with a professional standard (odds ratio = 2.15, 95% confidence interval = 1.32–3.50). The law’s expectations of clinicians with respect to risk disclosure appear to vary geographically

Can the United States Afford a “No-Fault” System of Compensation for Medical Injury?

One of the key issues separating US critics of a no-fault alternative to the tort system for compensating victims of medical injury from supporters is its anticipated cost. Results from a study are presented that estimate the costs of a no-fault system, one that is similar to the system now in operation in Sweden, within the context of the US health care system

Isotopic substitution experiments in the hydrogenation of mandelonitrile over a carbon supported Pd catalyst: a nuclear magnetic resonance study

A mechanistic exploration of the liquid phase hydrogenation of the aromatic cyanohydrin mandelonitrile (C6H5CH(OH)CH2CN) over a carbon supported Pd catalyst to produce the primary amine, phenethylamine (C6H5CH2CH2NH2) is conducted. Prior examination showed the reaction to involve the production of the ketone intermediate 2-aminoacetophenone (C6H5C(O)CH2NH2), formed as a consequence of the presence of an acid catalysed tautomeric side reaction. The corresponding deuteration reaction, reported here and analysed by multinuclear NMR spectroscopy and mass spectrometry, is employed to further investigate accessible pathways. Examination of the resultant product distribution of the deuteration, and the location of deuterium incorporation establishes the role of a hydroxy-imine species as a key reaction intermediate. In addition, the acid catalysed tautomerism to the ketone is shown to be a reversible side reaction, but also a contributor to desired product formation. Moreover, an order for the three critical hydrogen consuming steps in phenethylamine formation is established. Hydrogenation of the nitrile functionality to afford the hydroxy-imine precedes hydrogenolysis of the hydroxyl group, with the final step being hydrogenation of the imine to form the target product, phenethylamine

Proteomic analysis of 14-3-3 zeta binding proteins in the mouse hippocampus.

14-3-3 proteins are ubiquitous molecular chaperones with important roles in brain development and neuronal function. Altered expression of 14-3-3 proteins has been reported in several neurologic and neurodegenerative disorders and identifying 14-3-3 binding proteins may provide important insights into the physiologic and pathophysiologic roles of these proteins. Particular interest has emerged on 14-3-3 zeta (ζ) in the setting of neuronal injury because reducing 14-3-3ζ levels triggers an endoplasmic reticulum stress-like response in neurons and increases vulnerability to excitotoxicity. Here we examined the subcellular distribution of 14-3-3ζ in the mouse hippocampus. We then used recombinant His-tagged 14-3-3ζ to pull-down interacting proteins from the mouse hippocampus followed by identification by liquid chromatography-mass spectrometry. 14-3-3ζ protein was present in the cytoplasm, microsomal compartment, nucleus and mitochondrial fractions of the mouse hippocampus. Recombinant 14-3-3ζ eluted 13 known 14-3-3 binding partners, including three other 14-3-3 isoforms, and 16 other proteins which have not previously been reported to bind 14-3-3ζ. The present study identifies potentially novel 14-3-3ζ binding proteins and contributes to defining the 14-3-3ζ interactome in the mouse brain

Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.Comment: paper + supporting information, total 35 pages, 15 figure