In the article, we analyse the impact of changing policy environments on the development of the third sector in Europe. Based on the results of systematic comparative research in eight European ...countries (Austria, Croatia, France, Germany, the Netherlands, Poland, Spain and the UK), we identify commonalities and differences. In a three-step analysis, we examine policy changes, effects on the third sector and responses by third sector organizations (TSOs) in the social domain. Overall, the third sector in Europe has proven resilient. However, not only have public and private funding decreased, the process for acquiring such funding has become more demanding for TSOs, as have requirements to be accountable. There are signs of a proliferation of more market-based, hybrid organizations. Despite this general trend towards marketization, the impact of policy changes varies across Europe with TSOs being better equipped to adapt and survive in countries where collaborative ties between the state and the third sector have traditionally been strong.
TMEM106B is a major risk factor for frontotemporal lobar degeneration with TDP‐43 pathology. TMEM106B localizes to lysosomes, but its function remains unclear. We show that TMEM106B knockdown in ...primary neurons affects lysosomal trafficking and blunts dendritic arborization. We identify microtubule‐associated protein 6 (MAP6) as novel interacting protein for TMEM106B. MAP6 over‐expression inhibits dendritic branching similar to TMEM106B knockdown. MAP6 knockdown fully rescues the dendritic phenotype of TMEM106B knockdown, supporting a functional interaction between TMEM106B and MAP6. Live imaging reveals that TMEM106B knockdown and MAP6 overexpression strongly increase retrograde transport of lysosomes in dendrites. Downregulation of MAP6 in TMEM106B knockdown neurons restores the balance of anterograde and retrograde lysosomal transport and thereby prevents loss of dendrites. To strengthen the link, we enhanced anterograde lysosomal transport by expressing dominant‐negative Rab7‐interacting lysosomal protein (RILP), which also rescues the dendrite loss in TMEM106B knockdown neurons. Thus, TMEM106B/MAP6 interaction is crucial for controlling dendritic trafficking of lysosomes, presumably by acting as a molecular brake for retrograde transport. Lysosomal misrouting may promote neurodegeneration in patients with TMEM106B risk variants.
Synopsis
GWAS studies identified TMEM106B a major risk factor for frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology. This study combines loss‐off‐function experiments, live‐imaging and proteomics to elucidate the function of the lysosomal protein TMEM106B in neurons.
Co‐immunoprecipitation experiments and mass‐spectrometry show that TMEM106B interacts with microtubule‐associated protein 6 (MAP6).
TMEM106B knockdown promotes retrograde transport of dendritic lysosomes and dendrite loss, which is phenocopied by MAP6 overexpression.
MAP6 knockdown rebalances dendritic trafficking of lysosomes and fully rescues the dendritic phenotype of TMEM106B knockdown.
Promoting anterograde lysosomal transport using dominant negative Rab7‐interacting lysosomal protein (RILP) rescues dendrite loss in TMEM106B knockdown neurons.
TMEM106B/MAP6 interaction controls dendritic branching, presumably by providing a molecular brake for retrograde dendritic trafficking of lysosomes.
GWAS studies identified TMEM106B a major risk factor for frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology. This study combines loss‐off‐function experiments, live‐imaging and proteomics to elucidate the function of the lysosomal protein TMEM106B in neurons.
The predictive coding model is rapidly gaining attention in schizophrenia research. It posits the neuronal computation of residual variance ('prediction error') between sensory information and ...top-down expectation through multiple hierarchical levels. Event-related potentials (ERP) reflect cortical processing stages that are increasingly interpreted in the light of the predictive coding hypothesis. Both mismatch negativity (MMN) and repetition suppression (RS) measures are considered a prediction error correlates based on error detection and error minimization, respectively.
Twenty-five schizophrenia patients and 25 healthy controls completed auditory tasks designed to elicit MMN and RS responses that were investigated using repeated measures models and strong spatio-temporal a priori hypothesis based on previous research. Separate correlations were performed for controls and schizophrenia patients, using age and clinical variables as covariates.
MMN and RS deficits were largely replicated in our sample of schizophrenia patients. Moreover, MMN and RS measures were strongly correlated in healthy controls, while no correlation was found in schizophrenia patients. Single-trial analyses indicated significantly lower signal-to-noise ratio during prediction error computation in schizophrenia.
This study provides evidence that auditory ERP components relevant for schizophrenia research can be reconciled in the light of the predictive coding framework. The lack of any correlation between the investigated measures in schizophrenia patients suggests a disruption of predictive coding mechanisms in general. More specifically, these results suggest that schizophrenia is associated with an irregular computation of residual variance between sensory input and top-down models, i.e. prediction error.
Various aspects of cortical face processing have been studied by assessing event related potentials (ERP). It has been described in the literature that mismatch negativity (MMN), a well-studied ERP, ...is not only modulated by sensory features but also emotional valence. However, the exact impact of emotion on the temporo-spatial profile of visual MMN during face processing remains inconsistent. By employing a sequential oddball paradigm using both neutral and emotional deviants, we were able to differentiate two distinct vMMN subcomponents. While an early subcomponent at 150–250 ms is elicited by emotional salient facial stimuli, the later subcomponent at 250–400 ms seems to reflect the detection of regularity violations in facial recognition per se, unaffected by emotional salience. Our results suggest that emotional valence is encoded in vMMN signal strength at an early stage of facial processing. Furthermore, we assume that of facial processing consists of temporo-spatially distinct, partially overlapping levels concerning different facial aspects.
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•A sequential face oddball paradigm was used to minimize low-level effects.•Emotional valences evoked different emotional vMMN signal strengths at 150-250 ms•General facial recognition was encoded at 250-400 ms•vMMN encodes emotional valence via signal strength and speed of onset.
Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian ...autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood-brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.
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