Allosteric regulation of exocyst: Discrete activation of tethering by two spatial signals.

The exocyst imparts spatial control during exocytic vesicle tethering through its interactions with proteins and lipids on the vesicle and the plasma membrane. One such interaction is with the vesicle tether Sro7, although the outcome of this interaction is poorly understood. Here, we describe how Sro7 binding to the Exo84 subunit results in activation of the exocyst complex which leads to an increase in avidity for the Rab GTPase Sec4 and an increase in exocyst-mediated vesicle tethering. Gain-of-function (GOF) mutations in Exo84 that mimic Sro7 activation replicate these biochemical changes and result in allosteric changes within the complex. Direct comparison of GOF mutants which mimic Sro7- and Rho/Cdc42-activation of the exocyst reveals distinct mechanisms and outcomes. We propose a model by which these two activation pathways reside within the same tethering complex but remain insulated from one another. Structural modeling suggests a related mechanism for Sro7 activation of the exocyst in yeast and Ral GTPase activation of the exocyst in animal cells.

Indigenous Social Enterprises and Health and Wellbeing: A Scoping Review and Conceptual Framework.

Indigenous people and communities are establishing social enterprises to address social disadvantage and overcome health inequities in their communities. This review sought to characterize the spectrum of Indigenous social enterprises in Australia, New Zealand, Canada, and the United States to identify the operational models and cultural values that underpin them and their impact on Indigenous health and wellbeing. The scoping review followed Arksey and O'Malley's six-stage methodological framework with recommended enhancements by Levac et al. underpinned by Indigenous Standpoint Theory, and an Indigenous advisory group to provide cultural oversight and direction. Of the 589 documents screened 115 documents were included in the review. A conceptual framework of seven different operational models of Indigenous social enterprises was developed based on differing levels of Indigenous ownership, control, and management: (1) individual, (2) collective, (3) delegative, (4) developmental, (5) supportive, (6) prescriptive and (7) paternalistic. Models with 100% Indigenous ownership and control were more likely to contribute to improved health and wellbeing by increasing self-determination and strengthening culture and promoting healing than others. Indigenous social enterprises could offer a more holistic and sustainable approach to health equity and health promotion than the siloed, programmatic model common in public health policy.

Vagal nerve stimulation in refractory epilepsy: the first 100 patients receiving vagal nerve stimulation at a pediatric epilepsy center.

OBJECTIVE: To determine the outcome of intermittent left vagal nerve stimulation on the first 100 consecutive patients treated at our pediatric epilepsy center. METHODS: Patients were identified by means of operating room records. Data collected described the patient's epilepsy, previous and subsequent therapies, adverse events, nonepileptic changes, and outcomes. RESULTS: Average age was 10.4 years; years of epilepsy, 8.5; total number of antiepileptic therapies, 8.4; and median monthly seizure frequency, 120. Data on seizure frequency at follow-up were available for 96 of the 100 patients. Forty-five percent of patients achieved greater than 50% reduction; and 18% had had no seizures for the last 6 months. Response was similar in patients with more than 7 years of refractory epilepsy as compared with patients with a shorter history. Magnet-generated, on-demand current reduced seizure intensity in almost half of the patients with available data. Generator infections occurred in 3 patients. Twenty-four patients had their generators removed. Subsequently, 2 of these patients died. CONCLUSIONS: Seizure reduction was the same in patients younger than 12 years and 12 years or older and in patients with shorter and longer histories of refractory epilepsy. Adverse effects were few in this population, particularly in those younger than 12 years. Vagal nerve stimulation appears to be a relatively safe and potentially effective treatment for children with severely intractable epilepsy.