Molecular and functional characterization of an evolutionarily conserved CREB-binding protein in the Lymnaea CNS.

In eukaryotes, CREB-binding protein (CBP), a coactivator of CREB, functions both as a platform for recruiting other components of the transcriptional machinery and as a histone acetyltransferase (HAT) that alters chromatin structure. We previously showed that the transcriptional activity of cAMP-responsive element binding protein (CREB) plays a crucial role in neuronal plasticity in the pond snail Lymnaea stagnalis. However, there is no information on the molecular structure and HAT activity of CBP in the Lymnaea central nervous system (CNS), hindering an investigation of its postulated role in long-term memory (LTM). Here, we characterize the Lymnaea CBP (LymCBP) gene and identify a conserved domain of LymCBP as a functional HAT. Like CBPs of other species, LymCBP possesses functional domains, such as the KIX domain, which is essential for interaction with CREB and was shown to regulate LTM. In-situ hybridization showed that the staining patterns of LymCBP mRNA in CNS are very similar to those of Lymnaea CREB1. A particularly strong LymCBP mRNA signal was observed in the cerebral giant cell (CGC), an identified extrinsic modulatory interneuron of the feeding circuit, the key to both appetitive and aversive LTM for taste. Biochemical experiments using the recombinant protein of the LymCBP HAT domain showed that its enzymatic activity was blocked by classical HAT inhibitors. Preincubation of the CNS with such inhibitors blocked cAMP-induced synaptic facilitation between the CGC and an identified follower motoneuron of the feeding system. Taken together, our findings suggest a role for the HAT activity of LymCBP in synaptic plasticity in the feeding circuitry.

Selective Neuromodulation of the Vagus Nerve.

Vagus nerve stimulation (VNS) is an effective technique for the treatment of refractory epilepsy and shows potential for the treatment of a range of other serious conditions. However, until now stimulation has generally been supramaximal and non-selective, resulting in a range of side effects. Selective VNS (sVNS) aims to mitigate this by targeting specific fiber types within the nerve to produce functionally specific effects. In recent years, several key paradigms of sVNS have been developed-spatially selective, fiber-selective, anodal block, neural titration, and kilohertz electrical stimulation block-as well as various stimulation pulse parameters and electrode array geometries. sVNS can significantly reduce the severity of side effects, and in some cases increase efficacy of the treatment. While most studies have focused on fiber-selective sVNS, spatially selective sVNS has demonstrated comparable mitigation of side-effects. It has the potential to achieve greater specificity and provide crucial information about vagal nerve physiology. Anodal block achieves strong side-effect mitigation too, but is much less specific than fiber- and spatially selective paradigms. The major hurdle to achieving better selectivity of VNS is a limited knowledge of functional anatomical organization of vagus nerve. It is also crucial to optimize electrode array geometry and pulse shape, as well as expand the applications of sVNS beyond the current focus on cardiovascular disease.

Promoting women's and children's health through community groups in low-income and middle-income countries: a mixed-methods systematic review of mechanisms, enablers and barriers.

INTRODUCTION: Community mobilisation through group activities has been used to improve women's and children's health in a range of low-income and middle-income contexts, but the mechanisms through which it works deserve greater consideration. We did a mixed-methods systematic review of mechanisms, enablers and barriers to the promotion of women's and children's health in community mobilisation interventions. METHODS: We searched for theoretical and empirical peer-reviewed articles between January 2000 and November 2018. First, we extracted and collated proposed mechanisms, enablers and barriers into categories. Second, we extracted and synthesised evidence for them using narrative synthesis. We assessed risk of bias with adapted Downs and Black and Critical Appraisal Skills Programme checklists. We assigned confidence grades to each proposed mechanism, enabler and barrier. RESULTS: 78 articles met the inclusion criteria, of which 39 described interventions based on a participatory group education model, 19 described community-led structural interventions to promote sexual health in marginalised populations and 20 concerned other types of intervention or multiple interventions at once. We did not have high confidence in any mechanism, enabler or barrier. Two out of 15 proposed mechanisms and 10 out of 12 proposed enablers and barriers reached medium confidence. A few studies provided direct evidence relating proposed mechanisms, enablers or barriers to health behaviours or health outcomes. Only two studies presented mediation or interaction analysis for a proposed mechanism, enabler or barrier. CONCLUSION: We uncovered multiple proposed mechanisms, enablers and barriers to health promotion through community groups, but much work remains to provide a robust evidence base for proposed mechanisms, enablers and barriers. PROSPERO REGISTRATION NUMBER: CRD42018093695.