On the origin of proteins in human drusen : the meet, greet and stick hypothesis

This research was part-supported by de Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), de Stichting Blinden-Penning, de Gelderse Blinden Stichting, de Landelijke Stichting voor Blinden en Slechtzienden (LSBS), Stichting Oogfonds Nederland, Stichting MD Fonds and Stichting Retina Nederland Fonds (represented by Uitzicht, grants 2011-6 and 2014-7 to A.A.B.), de Rotterdamse Stichting Blindenbelangen (RSB), de Haagse Stichting Blindenhulp, Stichting Lijf en Leven, Stichting voor Ooglijders (to A.A.B.); ZonMW grant nr 446001002 (to A.A.B. and C.K.); the Bill Brown Charitable Trust, Moorfields Eye Hospital Special Trustees, Mercer Fund from Fight for Sight, the Eye-Risk project funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634479 (I.L. and E.E.), Fight for Sight project grant (I.L. and A.S.), the Bright Focus Foundation grant nr M2015370 (to SMH).Retinal drusen formation is not only a clinical hallmark for the development of age-related macular degeneration (AMD) but also for other disorders, such as Alzheimer's disease and renal diseases. The initiation and growth of drusen is poorly understood. Attention has focused on lipids and minerals, but relatively little is known about the origin of drusen-associated proteins and how they are retained in the space between the basal lamina of the retinal pigment epithelium and the inner collagenous layer space (sub-RPE-BL space). While some authors suggested that drusen proteins are mainly derived from cellular debris from processed photoreceptor outer segments and the RPE, others suggest a choroidal cell or blood origin. Here, we reviewed and supplement the existing literature on the molecular composition of the retina/choroid complex, to gain a more complete understanding of the sources of proteins in drusen. These “drusenomics” studies showed that a considerable proportion of currently identified drusen proteins is uniquely originating from the blood. A smaller, but still large fraction of drusen proteins comes from both blood and/or RPE. Only a small proportion of drusen proteins is uniquely derived from the photoreceptors or choroid. We next evaluated how drusen components may “meet, greet and stick” to each other and/or to structures like hydroxyapatite spherules to form macroscopic deposits in the sub-RPE-BL space. Finally, we discuss implications of our findings with respect to the previously proposed homology between drusenogenesis in AMD and plaque formation in atherosclerosis.PostprintPeer reviewe

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

Purpose: The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were systematically injected with various doses of sodium iodate (SI). After injection, the retinal structure and visual function were non-invasively characterized over time to obtain in-depth data on the suitability of these models for studying experimental therapies for retinal degenerative diseases, such as dry AMD. Methods: SI was injected into the tail vein (i.v.) using a series of doses (0–70 mg/kg) in adolescent C57BL/6J mice and Brown Norway rats. The retinal structure and function were assessed non-invasively at baseline (day 1) and at several time points (1–3, 5, and 10-weeks) post-injection by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and electroretinography (ERG). Results: After the SI injection, retinal degeneration in mice and rats yielded similar results. The lowest dose (10 mg/kg) resulted in non-detectable structural or functional effects. An injection with 20 mg/kg SI did not result in an evident retinal degeneration as judged from the OCT data. In contrast, the ERG responses were temporarily decreased but returned to baseline within two-weeks. Higher doses (30, 40, 50, and 70 mg/kg) resulted in moderate to severe structural RPE and retinal injury and decreased the ERG amplitudes, indicating visual impairment in both mice and rat strains. Conclusions: After the SI injections, we observed dose-dependent structural and functional pathological effects on the retinal pigment epithelium (RPE) and retina in the pigmented mouse and rat strains that were used in this study. Similar effects were observed in both species. In particular, a dose of 30 mg/kg seems to be suitable for future studies on developing experimental therapies. These relatively easily induced non-inherited models may serve as useful tools for evaluating novel therapies for RPE-related retinal degenerations, such as AMD

Articulatory Suppression Effects on Induced Rumination

International audienceThis study explores whether the speech motor system is involved in verbal rumination, a particular kind of inner speech. The motor simulation hypothesis considers inner speech as an action, accompanied by simulated speech percepts, that would as such involve the speech motor system. If so, we could expect verbal rumination to be disrupted by concurrent involvement of the speech apparatus. We recruited 106 healthy adults and measured their self-reported level of rumination before and after a rumination induction, as well as after five minutes of a subsequent motor task (either an articulatory suppression -silent mouthing- task or a finger tapping control task). We also evaluated to what extent ruminative thoughts were experienced with a verbal quality or in another modality (e.g., visual images, non-speech sounds). Self-reported levels of rumination showed a decrease after both motor activities (silent mouthing and finger-tapping), with only a slightly stronger decrease after the articulatory suppression than the control task. The rumination level decrease was not moderated by the modality of the ruminative thoughts. We discuss these results within the framework of verbal rumination as simulated speech and suggest alternative ways to test the engagement of the speech motor system in verbal rumination. Pre-registered protocol, preprint, data, as well as reproducible code and figures are available at: https://osf.io/3bh67/

Dissociating facial electromyographic correlates of visual and verbal induced rumination

International audienc

Environmental assessment of digestate treatment technologies using LCA methodology

Zirconia is a promising metal-free framework material that can be used to construct all-ceramic resin-bonded restorations in modern minimally invasive dentistry. The lack of a durable bond to zirconia is the major limitation against its widespread use. A technique to promote adhesion to the zirconia surface has thus been actively sought in dental materials research. Selective infiltration etching (SIE) has emerged as a method of conditioning that creates a highly retentive zirconia surface. This in vitro pilot study tested a novel adhesion procedure in which two newly engineered silane-based zirconia primers were combined with the SIE method. Zirconia discs were SIE-surface-treated, coated with one of the 2 zirconia primers, and bonded to composite resin discs. Primer activation (hydrolysis) was monitored by Fourier transform infrared (FTIR) spectroscopy. The bilayered specimens were sectioned into microbars and subjected to the microtensile bond strength test. As-sintered zirconia discs served as controls. Surface analysis of zirconia specimens was carried out using photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). Zirconia specimens that had been treated with both SIE and primers had a significantly higher (ANOVA) zirconia resin bond strength (40.6 MPa, SD 5.8 MPa) than control specimens (2.6 MPa, SD 3.0 MPa; p < 0.05, F = 13.8, ANOVA). Controls also exhibited spontaneous failure during sectioning. Additionally, the interfacial failure rate was lower for the specimens subjected to the new combined surface treatment than for controls. The novel combined method of surface treatment method might open new opportunities for enhanced adhesion of resin-bonded zirconia restorations

Orofacial electromyographic correlates of induced verbal rumination

Rumination is predominantly experienced in the form of repetitive verbal thoughts. Verbal rumination is a particular case of inner speech. According to the Motor Simulation view, inner speech is a kind of motor action, recruiting the speech motor system. In this framework, we predicted an increase in speech muscle activity during rumination as compared to rest. We also predicted increased forehead activity, associated with anxiety during rumination. We measured electromyographic activity over the orbicularis oris superior and inferior, frontalis and flexor carpi radialis muscles. Results showed increased lip and forehead activity after rumination induction compared to an initial relaxed state, together with increased self-reported levels of rumination. Moreover, our data suggest that orofacial relaxation is more effective in reducing rumination than non-orofacial relaxation. Altogether, these results support the hypothesis that verbal rumination involves the speech motor system, and provide a promising psychophysiological index to assess the presence of verbal rumination

Orofacial electromyographic correlates of induced verbal rumination.

International audienceRumination is predominantly experienced in the form of repetitive verbal thoughts. Verbal rumination is a particular case of inner speech. According to the Motor Simulation view, inner speech is a kind of motor action, recruiting the speech motor system. In this framework, we predicted an increase in speech muscle activity during rumination as compared to rest. We also predicted increased forehead activity, associated with anxiety during rumination. We measured electromyographic activity over the orbicularis oris superior and inferior, frontalis and flexor carpi radialis muscles. Results showed increased lip and forehead activity after rumination induction compared to an initial relaxed state, together with increased self-reported levels of rumination. Moreover, our data suggest that orofacial relaxation is more effective in reducing rumination than non-orofacial relaxation. Altogether, these results support the hypothesis that verbal rumination involves the speech motor system, and provide a promising psychophysiological index to assess the presence of verbal rumination

A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models

The retinal pigment epithelium (RPE) and the adjacent light-sensitive photoreceptors form a single functional unit lining the back of the eye. Both cell layers are essential for normal vision. RPE degeneration is usually followed by photoreceptor degeneration and vice versa. There are currently almost no effective therapies available for RPE disorders such as Stargardt disease, specific types of retinitis pigmentosa, and age-related macular degeneration. RPE replacement for these disorders, especially in later stages of the disease, may be one of the most promising future therapies. There is, however, no consensus regarding the optimal RPE source, delivery strategy, or the optimal experimental host in which to test RPE replacement therapy. Multiple RPE sources, delivery methods, and recipient animal models have been investigated, with variable results. So far, a systematic evaluation of the (variables influencing) efficacy of experimental RPE replacement parameters is lacking. Here we investigate the effect of RPE transplantation on vision and vision-based behavior in animal models of retinal degenerated diseases. In addition, we aim to explore the effect of RPE source used for transplantation, the method of intervention, and the animal model which is used. Methods: In this study, we systematically identified all publications concerning transplantation of RPE in experimental animal models targeting the improvement of vision (e.g., outcome measurements related to the morphology or function of the eye). A variety of characteristics, such as species, gender, and age of the animals but also cell type, number of cells, and other intervention characteristics were extracted from all studies. A risk of bias analysis was performed as well. Subsequently, all references describing one of the following outcomes were analyzed in depth in this systematic review: a-, b-, and c-wave amplitudes, vision-based, thickness analyses based on optical coherence tomography (OCT) data, and transplant survival based on scanning laser ophthalmoscopy (SLO) data. Meta-analyses were performed on the a- and b-wave amplitudes from electroretinography (ERG) data as well as data from vision-based behavioral assays. Results: original research articles met the inclusion criteria after two screening rounds. Overall, most studies were categorized as unclear regarding the risk of bias, because many experimental details were poorly reported. Twenty-three studies reporting one or more of the outcome measures of interest were eligible for either descriptive (thickness analyses based on OCT data; n = 2) or meta-analyses. RPE transplantation significantly increased ERG a-wave (Hedges’ g 1.181 (0.471–1.892), n = 6) and b-wave (Hedges’ g 1.734 (1.295–2.172), n = 42) amplitudes and improved vision-based behavior (Hedges’ g 1.018 (0.826–1.209), n = 96). Subgroup analyses revealed a significantly increased effect of the use of young and adolescent animals compared to adult animals. Moreover, transplanting more cells (in the range of 105 versus in the range of 104) resulted in a significantly increased effect on vision-based behavior as well. The origin of cells mattered as well. A significantly increased effect was found on vision-based behavior when using ARPE-19 and OpRegen® RPE. Conclusions: This systematic review shows that RPE transplantation in animal models for retinal degeneration significantly increases a- and b- wave amplitudes and improves vision-related behavior. These effects appear to be more pronounced in young animals, when the number of transplanted cells is larger and when ARPE-19 and OpRegen® RPE cells are used. We further emphasize that there is an urgent need for improving the reporting and methodological quality of animal experiments, to make such studies more comparable

Preprint: Orofacial electromyographic correlates of induced verbal rumination

Rumination is predominantly experienced in the form of repetitive verbal thoughts. Verbal rumination is a particular case of inner speech. According to the Motor Simulation view, inner speech is a kind of motor action, recruiting the speech motor system. In this framework, we predicted an increase in speech muscle activity during rumination as compared to rest. We also predicted increased forehead activity, associated with anxiety during rumination. We measured electromyographic activity over the orbicularis oris superior and inferior, frontalis and flexor carpi radialis muscles. Results showed increased lip and forehead activity after rumination induction compared to an initial relaxed state, together with increased self-reported levels of rumination. Moreover, our data suggest that orofacial relaxation is more effective in reducing rumination than non-orofacial relaxation. Altogether, these results support the hypothesis that verbal rumination involves the speech motor system, and provide a promising psychophysiological index to assess the presence of verbal rumination