Identification of novel inner membrane complex and apical annuli proteins of the malaria parasite Plasmodium falciparum

The inner membrane complex (IMC) is a defining feature of apicomplexan parasites, which confers stability and shape to the cell, functions as a scaffolding compartment during the formation of daughter cells and plays an important role in motility and invasion during different life cycle stages of these single-celled organisms. To explore the IMC proteome of the malaria parasite Plasmodium falciparum we applied a proximity-dependent biotin identification (BioID)-based proteomics approach, using the established IMC marker protein Photosensitized INA-Labelled protein 1 (PhIL1) as bait in asexual blood-stage parasites. Subsequent mass spectrometry-based peptide identification revealed enrichment of 12 known IMC proteins and several uncharacterized candidate proteins. We validated nine of these previously uncharacterized proteins by endogenous GFP-tagging. Six of these represent new IMC proteins, while three proteins have a distinct apical localization that most likely represents structures described as apical annuli in Toxoplasma gondii. Additionally, various Kelch13 interacting candidates were identified, suggesting an association of the Kelch13 compartment and the IMC in schizont and merozoite stages. This work extends the number of validated IMC proteins in the malaria parasite and reveals for the first time the existence of apical annuli proteins in P. falciparum. Additionally, it provides evidence for a spatial association between the Kelch13 compartment and the IMC in late blood-stage parasites

Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report

Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solutionoriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory

Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report

Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory

[FGME 2015] "Fehlerfortpflanzung bei aus Messgrößen berechneten Werten in der Psychologie"

[FGME 2015

An evaluation of means of inquiry into the biological evolution of consciousness

How can the biological evolution and functions of consciousness be studied? The purpose of this thesis was to determine not only what means of inquiry are available to do so but also how good they are or, more specifically, how promising they are with respect to the research goal of giving a scientifically respectable evolutionary explanation of consciousness. Because no suitable or easily adaptable evaluation system or set of evaluative criteria was available, I constructed a systematic tool for evaluating the promise of means of inquiry. The evaluation tool has three dimensions--relevance, efficacy, and practicality--with two criteria each, which are assessed independently (except for the relevance criteria) and synthesised into dimensional and promise scores. This tool served to evaluate, and advise on, 23 means of inquiry that have been used in the investigation of the evolution of consciousness, including its adaptation status and evolutionary functions. The core of the thesis is formed by the evaluation tool and its application. After establishing the need for an evaluation of means of inquiry in this area and presenting the evaluation tool constructed for this purpose, I apply the tool to arguments that consciousness is an evolutionary adaptation, to general reasoning strategies, and to evolutionary strategies. This thesis core is preceded by a contextual introduction to consciousness and evolutionary theory and by the dismissal of some sceptical positions. It is followed by a comparative review of the evaluation results and an evaluation of the evaluation tool. The main contributions of this research consist of the promise evaluation tool for means of inquiry, which is underpinned by a new evaluative theory and available for use by other researchers; and, through the tool's application, an improved understanding of means of inquiry and recommendations about which of them to use for the present research goal

Frontoparietal activity and its structural connectivity in binocular rivalry

To understand the brain areas associated with visual awareness and their anatomical interconnections, we studied binocular rivalry with functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). Binocular rivalry occurs when one image is viewed by one eye and a different image by the other; it is experienced as perceptual alternations between the two images. Our first experiment addressed problems with a popular comparison condition, namely permanent suppression, by comparing rivalry with binocular fusion instead. We found an increased fMRI signal in right frontal, parietal, and occipital regions during rivalry viewing. The pattern of neural activity differed from findings of permanent suppression comparisons, except for adjacent activity in the right superior parietal lobule. This location was near fMRI signal changes related to reported rivalry alternations in our second experiment, indicating that neighbouring areas in the right parietal cortex may be involved in different components of rivalry. In our second experiment, we used probabilistic tractography to detect white matter fibres between right-hemispheric areas that showed event-related fMRI signal changes time-locked to reported perceptual alternations during rivalry viewing. Most of these functionally defined areas were linked by probabilistic fibre tracts, some of which followed long-distance connections such as the inferior occipitofrontal fasciculus. Corresponding anatomical pathways might mediate communication within the functional network associated with changes in conscious perception during binocular rivalry

The fiber tracts affected by the patient's lesion.

<p>The patient's acute lesion (a, yellow) and affected fibre tracts (purple) in the chronic brain, superimposed on the patient's fractional anisotropy image. The tracts include at the posterolateral edge of the pulvinar the inferior fronto-occipital fasciculus (b), which projects to the external capsule and the insula.</p

Egocentric reachable task.

<p>(a) schematic setup and illustration of the mean distance estimates of reachable stimuli; (b) estimates of T.R. (diamond) and control group (triangles) of the border of their peripersonal egocentric space.</p

T.R.'s neuropsychological test scores.

<p>Language: Boston naming test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-ThuillardColombo1" target="_blank">[45]</a>, Fluency test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Cardebat1" target="_blank">[46]</a>; Apraxia: sub-test CAMCOG <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Huppert1" target="_blank">[47]</a>; Agnosia: Protocole Montréal-Toulouse d'Evaluation des Gnosies Visuelles <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Agniel1" target="_blank">[48]</a>; Memory: Span (sub-test CAMCOG), 16 words (Grober and Buschke test, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-VanderLinden1" target="_blank">[49]</a>); Executive function: Luria test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Luria1" target="_blank">[50]</a>, Stroop <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Moroni1" target="_blank">[51]</a>, Trail Making Test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Tombaugh1" target="_blank">[52]</a>; Neglect <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Azouvi1" target="_blank">[53]</a>. Percentil: per.</p