Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete “clusters” of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents

The undervalued potential of positional therapy in position-dependent snoring and obstructive sleep apnea—a review of the literature

PURPOSE: Research during the past 10–20 years shows that positional therapy (PT) has a significant influence on the apnea–hypopnea index. These studies are predominantly performed as case series on a comparably small number of patients. Still, results have not found their way into the daily diagnostic and treatment routine. An average of 56 % of patients with obstructive sleep apnea (OSA) have position-dependent OSA (POSA), commonly defined as a difference of 50 % or more in apnea index between supine and non-supine positions. A great deal could be gained in treating patients with POSA with PT. The aim of this paper was to perform a thorough review of the literature on positional sleep apnea and its therapy. METHODS: A broad search strategy was run electronically in the MEDLINE and EMBASE databases using synonyms for position and sleep apnea. RESULTS: Sixteen studies were found which examined the effect of PT on OSA. In this literature review, we discuss the various techniques, results, and compliance rates. CONCLUSION: Long-term compliance for PT remains an issue, and although remarkable results have been shown using innovative treatment concepts for PT, there is room for both technical improvement of the devices and for further research

Modelling job crafting behaviours: Implications for work engagement

In this study among 206 employees (103 dyads), we followed the job demands–resources approach of job crafting to investigate whether proactively changing one’s work environment influences employee’s (actor’s) own and colleague s (partner’s) work engagement. Using social cognitive theory, we hypothesized that employees would imitate each other’s job crafting behaviours, and therefore influence each other’s work engagement. Results showed that the crafting of social and structural job resources, and the crafting of challenge job demands was positively related to own work engagement, whereas decreasing hindrance job demands was unrelated to own engagement. As predicted, results showed a reciprocal relationship between dyad members’ job crafting behaviours – each of the actor’s job crafting behaviours was positively related to the partner’s job crafting behaviours. Finally, employee’s job crafting was related to colleague’s work engagement through colleague’s job crafting, suggesting a modelling process

Inaugurating a Dutch Napoleon? Conservative criticism of the 1815 constitution of the United Kingdom of The Netherlands

International audienc

Provinciality and the Art World: The Midland Group 1961- 1977

This paper takes as its focus the Midland Group Gallery in order to first, make a case for the consideration of the geographies of art galleries. Second, highlight the importance of galleries in the context of cultural geographies of the sixties. Third, discuss the role of provinciality in the operation of art worlds. In so doing it explicates one set of geographies surrounding the gallery – those of the local, regional and international networks that connected to produce art works and art space. It reveals how the interactions between places and practices outside of metropolitan and regional hierarchies provides a more nuanced insight into how art worlds operated during the sixties, a period of growing internationalism of art, and how contested definitions of the provincial played an integral role in this. The paper charts the operations of the Midland Group Gallery and the spaces that it occupied to demonstrate how it was representative of a post-war discourse of provincialism and a corresponding re-evaluation of regional cultural activity

Mapping mangrove dynamics and colonization patterns at the Suriname coast using historic satellite data and the LandTrendr algorithm

This is the final version. Available from Elsevier via the DOI in this record. Mangroves play an important role in protecting coasts against wave energy and storms. Mangrove ecosystems provide important habitats for fauna and flora and are an important carbon sink. Loss of mangroves forest may lead to enhanced coastal erosion. Mangroves are complex ecosystems and processes of settling and development are not fully understood. Characterizing the rates and patterns of mangrove gains and losses is needed to better understand the functioning of mangrove ecosystems, how mangrove dynamics are linked to coastal morphological behaviour and how human interference with the coastal system impacts mangroves. Here we present a study of the mangrove ecosystems at the Suriname coast, which are relatively pristine and characterized by strong dynamics due to migrating mudbanks along the coast. Satellite images between 2000 and 2018, available in the historic satellite image archives, were analysed using the LandTrendr (Landsat-based detection of trends in disturbance and recovery) algorithm to identify locations of mangrove erosion, mangrove colonization, surface areas of change and patterns of settlement, as indicated by (sudden) changes in NDVI. The algorithm requires careful setting of various parameters for successful detection of (abrupt) temporal changes in mangrove coverage. The algorithm was evaluated on its robustness using various parameter settings. Results show the value of the timeseries of Landsat imagery to detect locations of coastal erosion of up to 50 m/yr and accretion where loss or settlement of mangroves is prevailing between 2000 and 2018. Locally differences are very large. An overall westward mangrove progression along the coast is apparent from the images and probably linked to mud bank migration. Various patterns of mangrove colonization and development such as arc-, zonal- and patch- arrangements were identified, although at some locations the Landsat resolution of 30 m is somewhat coarse to allow detailed analysis. The success and robustness of the LandTrendr algorithm are controlled by NDVI threshold values, number of allowed breakpoints in the timeseries and fitting parameters. The presented method requires further testing and evaluation but is a promising tool for semi-automatic detection of coastal mangrove erosion and colonization that can be applied to other mangrove ecosystems in the world. The satellite timeseries analyses generate valuable information on coastal dynamics, which is helpful to identify coastal areas prone to erosion and mangrove retreat and provide as such a valuable tool for coastal management and protection.NWO WOTRO Joint Sustainability Development Goal Research ProgramUtrecht University Bright Minds projec

Producing persuasive findings: Demystifying ethnographic textwork in strategy and organization research

Despite the importance and proliferation of ethnography in strategy and organization research, the central issue of how to present ethnographic findings has rarely been discussed. Yet, the narratives we craft to share our experience of the field are at the heart of ethnographic papers and provide the primary basis for our theorizing. In this article, we explain the “textwork” involved in writing persuasive findings. We provide an illustrative example of ethnographic data as it is recorded within fieldnotes and explain the necessary conceptual and writing work that must be done to render such data persuasive, drawing on published exemplars of ethnographic articles. This allows us to show how such texts, through various forms of writing and data representation, are transformed from raw fieldnotes to comprehensible findings. We conclude by asserting the value of these specifically ethnographic ways of presenting evidence, which are at odds with the canonical methods of data presentation in management studies

Human behaviour and economic growth: a psychocultural perspective on local and regional development

A renewed emphasis on behavioural traits has emerged as a means of explaining regional and local differences in economic performance and development. Given this, the aim of this study is to identify distinct local psychocultural behavioural profiles and to examine the extent to which these are associated with economic growth. Combining theories of community culture and personality psychology into a holistic spatially-oriented perspective, the paper argues that the types of human behaviour found across local places emerges from the co-evolution of cultural and personality factors. An empirical analysis of localities in Great Britain identifies and explores three underlying psychocultural profiles: Diverse Extraversion; Inclusive Amenability and Individual Commitment. It is found that inclusive amenable and individually committed psychocultural behaviour generally appear to hold back local economic growth, with the exception of recessionary periods. The reverse relationship is somewhat the case for diverse extravert behaviour. It is concluded that a better understanding of the holistic relationship and co-evolution of the cultural and psychological behavioural make-up of localities and regions has the potential to provide new insights into expected development outcomes as well as the forms of policy intervention that are required within regions and localities, each of which has its own individual psychocultural character