Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod

Understanding hepatitis C intervention success: qualitative findings from the HepCATT study

The United Kingdom has committed to eliminating viral hepatitis as a public health threat. Innovative interventions for marginalized populations are required to realize this goal. In 2016, the HepCATT study team implemented a complex hepatitis C (HCV) intervention in three English drug treatment services, with five controls. We report qualitative study findings from two intervention sites to explore intervention success and transferability potential. The intervention comprised multiple components, including a nurse facilitator, peer support and education initiatives. Qualitative data were generated at baseline (2014) and post-intervention (2016) at two sites through in-depth interviews, focus groups and observations. The 96 participants comprised drug service and intervention providers and clients with an injecting history. Data were triangulated and thematically analysed. Client engagement with a HCV treatment service rose from 16 at baseline to 147 in 2016. There was no comparable increase at the five control sites. Baseline testing and treatment barriers included the following: limited HCV knowledge; fear of diagnosis and treatment; precarious living circumstances and service-specific obstacles. Treatment engagement was aided by intervention timeliness; improved communication structures; personalized care; streamlined testing and treatment pathways; peer support. Multiple interrelated components influenced the increased levels of treatment engagement documented in HepCATT. The nurse facilitator, involved in implementation and innovation, was key to intervention success. Baseline barriers correspond with international literature—indicating transferability potential. Control data indicate that biomedical innovation alone is not sufficient to increase engagement among the most marginalized. Sustainable resourcing of community services is crucial to effect change

NF-Y recruitment of TFIID, multiple interactions with histone fold TAF(II)s

The nuclear factor y (NF-Y) trimer and TFIID contain histone fold subunits, and their binding to the CCAAT and Initiator elements of the major histocompatibility complex class II Ea promoter is required for transcriptional activation. Using agarose-electrophoretic mobility shift assay we found that NF-Y increases the affinity of holo-TFIID for Ea in a CCAAT- and Inr-dependent manner. We began to dissect the interplay between NF-Y- and TBP-associated factors PO1II (TAF(II)s)-containing histone fold domains in protein-protein interactions and transfections. hTAF(II)20, hTAF(II)28, and hTAF(II)18-hTAF(II)28 bind to the NF-Y B-NF-YC histone fold dimer; hTAF(II)80 and hTAF(II)31-hTAF(II)80 interact with the trimer but not with the NF-YB-NF-YC dimer. The histone fold alpha2 helix of hTAF(II)80 is not required for NF-Y association, as determined by interactions with the naturally occurring splice variant hTAF(II)80delta. Expression of hTAF(II)28 and hTAF(II)18 in mouse cells significantly and specifically reduced NF-Y activation in GAL4-based experiments, whereas hTAF,120 and hTAF(II)135 increased it. These results indicate that NF-Y (i) recruits purified holo-TFIID in vitro and (ii) can associate multiple TAF(II)s, potentially accommodating different core promoter architectures

Adjuncts or adversaries to shared decision-making? Applying the Integrative Model of behavior to the role and design of decision support interventions in healthcare interactions

Background A growing body of literature documents the efficacy of decision support interventions (DESI) in helping patients make informed clinical decisions. DESIs are frequently described as an adjunct to shared decision-making between a patient and healthcare provider, however little is known about the effects of DESIs on patients' interactional behaviors-whether or not they promote the involvement of patients in decisions. Discussion Shared decision-making requires not only a cognitive understanding of the medical problem and deliberation about the potential options to address it, but also a number of communicative behaviors that the patient and physician need to engage in to reach the goal of making a shared decision. Theoretical models of behavior can guide both the identification of constructs that will predict the performance or non-performance of specific behaviors relevant to shared decision-making, as well as inform the development of interventions to promote these specific behaviors. We describe how Fishbein's Integrative Model (IM) of behavior can be applied to the development and evaluation of DESIs. There are several ways in which the IM could be used in research on the behavioral effects of DESIs. An investigator could measure the effects of an intervention on the central constructs of the IM - attitudes, normative pressure, self-efficacy, and intentions related to communication behaviors relevant to shared decision-making. However, if one were interested in the determinants of these domains, formative qualitative research would be necessary to elicit the salient beliefs underlying each of the central constructs. Formative research can help identify potential targets for a theory-based intervention to maximize the likelihood that it will influence the behavior of interest or to develop a more fine-grained understanding of intervention effects. Summary Behavioral theory can guide the development and evaluation of DESIs to increase the likelihood that these will prepare patients to play a more active role in the decision-making process. Self-reported behavioral measures can reduce the measurement burden for investigators and create a standardized method for examining and reporting the determinants of communication behaviors necessary for shared decision-making

In search of 'managerial work' : past, present and future of an analytical category

Based on a comprehensive review of literature, the paper examines how ‘managerial work’ as a fluid analytical category has been approached methodologically, theoretically, and empirically over the last 60+ years. In particular, we highlight the existence of competing scholarly understandings regarding its nature, performance, meaning, and politics. We suggest that subsequent empirical investigations have too often worked, methodologically and theoretically, to slot in, and thus effectively reduce, the term to a particular pre-existing box, rather than exploring open-endedly what and how, but also why of ‘managerial work’ as a distinct mode of situated ordering. Having represented the concept’s past and present by identifying four distinct research approaches reflected in representative publications, we suggest more attention should be devoted to a mode of analytical departure that promises to directly address suggested shortcomings in the literature. Specifically, we argue that much could be gained if contemporary notions of practice are brought into the study of managerial work. To this end, we outline the contours of a practice-based approach as a sensitizing framework for understanding managerial work, by highlighting the situated, relational, sociomaterial, meaning-making, and consequence-oriented analytical foci the approach suggests, and suggesting a number of conjoint research questions, as well as acknowledging subsequent limitations

Barbarians at the British Museum: Anglo-Saxon Art, Race and Religion

A critical historiographical overview of art historical approaches to early medieval material culture, with a focus on the British Museum collections and their connections to religion