Are there specific design elements of choice experiments and types of people that influence choice response certainty?

The development of more realistic choice experiments has taken on board a number of suggestions in the broader hypothetical bias literature. One issue, in particular, is the increasing interest in finding ways to bridge the gap between the stated choice response and real choosing, as a way of increasing the confidence with which an individual would hypothetically purchase or use an alternative that is actually chosen in the choice experiment. In this paper we investigate the relationship between the respondent's response to a certainty question, defined on a 1-10 scale of surety, and features of the choice experiment that may have a bearing on the degree of confidence that can be placed on the stated choice, controlling for exogenous effects such as socioeconomic characteristics and attitudes to vehicle emissions. The focus on response certainty in this paper is as an external validity test. We find, using a generalised ordered logit model, compelling evidence that the number of acceptable alternatives and hence associated levels of attributes, together with the contrast of attribute levels of each designed alternative relative to an experienced status quo (or reference) alternative, play an important role in establishing certainty of response in a real market. The evidence should be taken on board in the future design of more realistic choice experiments

No Increased Suggestibility to Placebo in Functional Neurological Disorder

BACKGROUND AND PURPOSE: On the basis of occasional strong placebo responses, increased susceptibility to placebo has been proposed as a characteristic of functional neurological disorder (FND). The aim of this study was to clarify whether people with FND have a stronger placebo analgesic response than healthy controls. METHODS: A study using a classic placebo paradigm, with additional conditioning and open-label components, was performed in 30 patients with FND, and in 30 healthy controls. Ratings of mildly to moderately painful electrotactile stimuli were compared before and after the application of a placebo “anaesthetic” cream versus a control cream, after an additional conditioning exposure, and after full disclosure (open-label component). RESULTS: Pain intensity ratings at the placebo compared to the control site were similarly reduced in both groups. The conditioning exposure had no additional effect. After placebo disclosure a residual analgesic effect remained. CONCLUSION: Patients with FND did not have stronger placebo responses than healthy controls. The notion of generally increased suggestibility or increased suggestibility to placebo in FND seems mistaken. Instead, occasional dramatic placebo responses may occur because functional symptoms are inherently more changeable than those due to organic disease

No Increased Suggestibility to Placebo in Functional Neurological Disorder

BACKGROUND AND PURPOSE: On the basis of occasional strong placebo responses, increased susceptibility to placebo has been proposed as a characteristic of functional neurological disorder (FND). The aim of this study was to clarify whether people with FND have a stronger placebo analgesic response than healthy controls. METHODS: A study using a classic placebo paradigm, with additional conditioning and open-label components, was performed in 30 patients with FND, and in 30 healthy controls. Ratings of mildly to moderately painful electrotactile stimuli were compared before and after the application of a placebo “anaesthetic” cream versus a control cream, after an additional conditioning exposure, and after full disclosure (open-label component). RESULTS: Pain intensity ratings at the placebo compared to the control site were similarly reduced in both groups. The conditioning exposure had no additional effect. After placebo disclosure a residual analgesic effect remained. CONCLUSION: Patients with FND did not have stronger placebo responses than healthy controls. The notion of generally increased suggestibility or increased suggestibility to placebo in FND seems mistaken. Instead, occasional dramatic placebo responses may occur because functional symptoms are inherently more changeable than those due to organic disease

Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the wake of the COVID-19 pandemic. Increasing resistance to gyrase-targeting second-line fluoroquinolone antibiotics indicates the necessity to develop both novel therapeutics and our understanding of M. tuberculosis growth during infection. ParDE toxin–antitoxin systems also target gyrase and are regulated in response to both host-associated and drug-induced stress during infection. Here, we present microbiological, biochemical, structural, and biophysical analyses exploring the ParDE1 and ParDE2 systems of M. tuberculosis H37Rv. The structures reveal conserved modes of toxin–antitoxin recognition, with complex-specific interactions. ParDE1 forms a novel heterohexameric ParDE complex, supported by antitoxin chains taking on two distinct folds. Curiously, ParDE1 exists in solution as a dynamic equilibrium between heterotetrameric and heterohexameric complexes. Conditional remodelling into higher order complexes can be thermally driven in vitro. Remodelling induces toxin release, tracked through concomitant inhibition and poisoning of gyrase activity. Our work aids our understanding of gyrase inhibition, allowing wider exploration of toxin–antitoxin systems as inspiration for potential therapeutic agents

Nuclear pore assembly proceeds by an inside-out extrusion of the nuclear envelope

The nuclear pore complex (NPC) mediates nucleocytoplasmic transport through the nuclear envelope. How the NPC assembles into this double membrane boundary has remained enigmatic. Here, we captured temporally staged assembly intermediates by correlating live cell imaging with high-resolution electron tomography and super-resolution microscopy. Intermediates were dome-shaped evaginations of the inner nuclear membrane (INM), that grew in diameter and depth until they fused with the flat outer nuclear membrane. Live and super-resolved fluorescence microscopy revealed the molecular maturation of the intermediates, which initially contained the nuclear and cytoplasmic ring component Nup107, and only later the cytoplasmic filament component Nup358. EM particle averaging showed that the evagination base was surrounded by an 8-fold rotationally symmetric ring structure from the beginning and that a growing mushroomshaped density was continuously associated with the deforming membrane. Quantitative structural analysis revealed that interphase NPC assembly proceeds by an asymmetric inside-out extrusion of the INM

Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach

The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity. © 2014 American Chemical Society

Valuing travel time changes: a case of short-term or long-term choices?

The valuation of travel time is of crucial importance in many transport decisions. Most studies make use of data framed around short-term decisions such as route choice. However, people may have a greater ability to trade time and money in a longer term setting, such as when considering changes in residential or employment locations. We study the value of travel time in both the short and long-term, finding differences in the valuations. Given the importance of these valuations for policy making, our results call for more research into how time-cost trade-offs should be represented with stated preference

Grassmannian flows and applications to nonlinear partial differential equations

We show how solutions to a large class of partial differential equations with nonlocal Riccati-type nonlinearities can be generated from the corresponding linearized equations, from arbitrary initial data. It is well known that evolutionary matrix Riccati equations can be generated by projecting linear evolutionary flows on a Stiefel manifold onto a coordinate chart of the underlying Grassmann manifold. Our method relies on extending this idea to the infinite dimensional case. The key is an integral equation analogous to the Marchenko equation in integrable systems, that represents the coodinate chart map. We show explicitly how to generate such solutions to scalar partial differential equations of arbitrary order with nonlocal quadratic nonlinearities using our approach. We provide numerical simulations that demonstrate the generation of solutions to Fisher--Kolmogorov--Petrovskii--Piskunov equations with nonlocal nonlinearities. We also indicate how the method might extend to more general classes of nonlinear partial differential systems.Comment: 26 pages, 2 figure

Measuring Dysfunctional Attitudes in the General Population: The Dysfunctional Attitude Scale (form A) Revised

The Dysfunctional Attitude Scale (DAS) was designed to measure the intensity of dysfunctional attitudes, a hallmark feature of depression. Various exploratory factor analytic studies of the DAS form A (DAS-A) yielded mixed results. The current study was set up to compare the fit of various factor models. We used a large community sample (N = 8,960) to test the previously proposed factor models of the DAS-A using confirmatory factor analysis. The retained model of the DAS-A was subjected to reliability and validity analyses. All models showed good fit to the data. Finally, a two-factor solution of the DAS-A was retained, consisting of 17 items. The factors demonstrated good reliability and convergent construct validity. Significant associations were found with depression. Norm-scores were presented. We advocate the use of a 17-item DAS-A, which proved to be useful in measuring dysfunctional beliefs. On the basis of previous psychometric studies, our study provides solid evidence for a two-factor model of the DAS-A, consisting of ‘dependency’ and ‘perfectionism/performance evaluation’

Automated Detection of Cortical Lesions in Multiple Sclerosis Patients with 7T MRI

The automated detection of cortical lesions (CLs) in patients with multiple sclerosis (MS) is a challenging task that, despite its clinical relevance, has received very little attention. Accurate detection of the small and scarce lesions requires specialized sequences and high or ultra- high field MRI. For supervised training based on multimodal structural MRI at 7T, two experts generated ground truth segmentation masks of 60 patients with 2014 CLs. We implemented a simplified 3D U-Net with three resolution levels (3D U-Net-). By increasing the complexity of the task (adding brain tissue segmentation), while randomly dropping input channels during training, we improved the performance compared to the baseline. Considering a minimum lesion size of 0.75 μL, we achieved a lesion-wise cortical lesion detection rate of 67% and a false positive rate of 42%. However, 393 (24%) of the lesions reported as false positives were post-hoc confirmed as potential or definite lesions by an expert. This indicates the potential of the proposed method to support experts in the tedious process of CL manual segmentation