Docking of LDCVs Is Modulated by Lower Intracellular [Ca2+] than Priming

Many regulatory steps precede final membrane fusion in neuroendocrine cells. Some parts of this preparatory cascade, including fusion and priming, are dependent on the intracellular Ca2+ concentration ([Ca2+]i). However, the functional implications of [Ca2+]i in the regulation of docking remain elusive and controversial due to an inability to determine the modulatory effect of [Ca2+]i. Using a combination of TIRF-microscopy and electrophysiology we followed the movement of large dense core vesicles (LDCVs) close to the plasma membrane, simultaneously measuring membrane capacitance and [Ca2+]i. We found that a free [Ca2+]i of 700 nM maximized the immediately releasable pool and minimized the lateral mobility of vesicles, which is consistent with a maximal increase of the pool size of primed LDCVs. The parameters that reflect docking, i.e. axial mobility and the fraction of LDCVs residing at the plasma membrane for less than 5 seconds, were strongly decreased at a free [Ca2+]i of 500 nM. These results provide the first evidence that docking and priming occur at different free intracellular Ca2+ concentrations, with docking efficiency being the most robust at 500 nM

Transgenic Overexpression of the Type I Isoform of Neuregulin 1 Affects Working Memory and Hippocampal Oscillations but not Long-term Potentiation

Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1tg-type I) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1tg-type I mice showed normal memory performance, but in older NRG1tg-type I mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1tg-type I mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1tg-type I mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

What does the audience experience as valuable local Journalism? Approaching local news quality from a user's perspective: Approaching local news quality from a user's perspective

This chapter addresses local news habits and preferences from an audience perspective. Drawing upon audience research done over a period of ten years in the Netherlands and placed in context using international research results, the notion of ‘valuable journalism’ is suggested as a conceptual bridge between what is usually defined as quality journalism (by journalists and users) and what users actually experience as local news quality. The findings suggest that giving more attention to specific topics (nature, environmental issues, history, safety and quality of care) and putting more emphasis on five news approaches (reciprocity and audience responsiveness as core to local news organisations’ business model, learning about the area, telling stories from within, facilitating regional orientation and honouring complexity) will provide news users with a more satisfying news experience for which they are willing to pay in money and/or attention

What Does the Audience Experience as Valuable Local Journalism?: Approaching local news quality from a user’s perspective

This chapter addresses local news habits and preferences from an audience perspective. Drawing upon audience research done over a period of ten years in the Netherlands and placed in context using international research results, the notion of ‘valuable journalism’ is suggested as a conceptual bridge between what is usually defined as quality journalism (by journalists and users) and what users actually experience as local news quality. The findings suggest that giving more attention to specific topics (nature, environmental issues, history, safety and quality of care) and putting more emphasis on five news approaches (reciprocity and audience responsiveness as core to local news organisations’ business model, learning about the area, telling stories from within, facilitating regional orientation and honouring complexity) will provide news users with a more satisfying news experience for which they are willing to pay in money and/or attention

Sourcing the Sources : An analysis of the use of Twitter and Facebook as a journalistic source over 10 years in The New York Times, The Guardian, and Süddeutsche Zeitung

Social media today are playing a more important role as a news source than ever before. Yet, there have been no longitudinal studies on journalists’ sourcing practices in recent years that allow us to consider the mechanisms of innovation diffusion. Comparative studies of different social platforms in different media systems are just as rare. We therefore examine the use of Facebook and Twitter as journalistic sources in newspapers of three countries. A main finding is that, after a period of stagnation at the beginning of this decade, the use of social media sources has resurged massively in recent years. The patterns of this second rise of social media in journalism are almost identical in the analyzed newspapers. A comparison of the platforms has shown that Twitter is more commonly used as a news source than Facebook. Compared to Facebook, Twitter is primarily used as an elite channel. An unsupervised topic clustering approach (LDA) also revealed that the issues on which social media are sourced and the quantities of social media references are similar in The New York Times and The Guardian. In Süddeutsche Zeitung, however, journalists source social media considerably less, and in different thematic contexts

What Are the Brain Mechanisms Underling Syntactic Operations?

International audienceThis chapter summarizes the extensive discussions that took place during the Forum as well as the subsequent months thereafter. It assesses current understanding of the neuronal mechanisms that underlie syntactic structure and processing.... It is posited that to understand the neurobiology of syntax, it might be worthwhile to shift the balance from comprehension to syntactic encoding in language productio