Mechanism of Notch Pathway Activation and Its Role in the Regulation of Olfactory Plasticity in Drosophila melanogaster

The neural plasticity of sensory systems is being increasingly recognized as playing a role in learning and memory. We have previously shown that Notch, part of an evolutionarily conserved intercellular signaling pathway, is required in adult Drosophila melanogaster olfactory receptor neurons (ORNs) for the structural and functional plasticity of olfactory glomeruli that is induced by chronic odor exposure. In this paper we address how long-term exposure to odor activates Notch and how Notch in conjunction with chronic odor mediates olfactory plasticity. We show that upon chronic odor exposure a non-canonical Notch pathway mediates an increase in the volume of glomeruli by a mechanism that is autonomous to ORNs. In addition to activating a pathway that is autonomous to ORNs, chronic odor exposure also activates the Notch ligand Delta in second order projection neurons (PNs), but this does not appear to require acetylcholine receptor activation in PNs. Delta on PNs then feeds back to activate canonical Notch signaling in ORNs, which restricts the extent of the odor induced increase in glomerular volume. Surprisingly, even though the pathway that mediates the increase in glomerular volume is autonomous to ORNs, nonproductive transsynaptic Delta/Notch interactions that do not activate the canonical pathway can block the increase in volume. In conjunction with chronic odor, the canonical Notch pathway also enhances cholinergic activation of PNs. We present evidence suggesting that this is due to increased acetylcholine release from ORNs. In regulating physiological plasticity, Notch functions solely by the canonical pathway, suggesting that there is no direct connection between morphological and physiological plasticity

Mechanism of Notch Pathway Activation and Its Role in the Regulation of Olfactory Plasticity in Drosophila melanogaster

The neural plasticity of sensory systems is being increasingly recognized as playing a role in learning and memory. We have previously shown that Notch, part of an evolutionarily conserved intercellular signaling pathway, is required in adult Drosophila melanogaster olfactory receptor neurons (ORNs) for the structural and functional plasticity of olfactory glomeruli that is induced by chronic odor exposure. In this paper we address how long-term exposure to odor activates Notch and how Notch in conjunction with chronic odor mediates olfactory plasticity. We show that upon chronic odor exposure a non-canonical Notch pathway mediates an increase in the volume of glomeruli by a mechanism that is autonomous to ORNs. In addition to activating a pathway that is autonomous to ORNs, chronic odor exposure also activates the Notch ligand Delta in second order projection neurons (PNs), but this does not appear to require acetylcholine receptor activation in PNs. Delta on PNs then feeds back to activate canonical Notch signaling in ORNs, which restricts the extent of the odor induced increase in glomerular volume. Surprisingly, even though the pathway that mediates the increase in glomerular volume is autonomous to ORNs, nonproductive transsynaptic Delta/Notch interactions that do not activate the canonical pathway can block the increase in volume. In conjunction with chronic odor, the canonical Notch pathway also enhances cholinergic activation of PNs. We present evidence suggesting that this is due to increased acetylcholine release from ORNs. In regulating physiological plasticity, Notch functions solely by the canonical pathway, suggesting that there is no direct connection between morphological and physiological plasticity

Validating the predictive ability of the 2MACE score for major adverse cardiovascular events in patients with atrial fibrillation: results from phase II/III of the GLORIA-AF registry

The 2MACE score was specifically developed as a risk-stratification tool in atrial fibrillation (AF) to predict cardiovascular outcomes. We evaluated the predictive ability of the 2MACE score in the GLORIA-AF registry. All eligible patients from phase II/III of the prospective global GLORIA-AF registry were included. Major adverse cardiac events (MACEs) were defined as the composite outcome of stroke, myocardial infarction and cardiovascular death. Cox proportional hazards were used to examine the relationship between the 2MACE score and study outcomes. Predictive capability of the 2MACE score was investigated using receiver-operating characteristic curves. A total of 25,696 patients were included (mean age 71 years, female 44.9%). Over 3 years, 1583 MACEs were recorded. Patients who had MACE were older, with more cardiovascular risk factors and were less likely to be managed using a rhythm-control strategy. The median 2MACE score in the MACE and non-MACE groups were 2 (IQR 1-3) and 1 (IQR 0-2), respectively (p < 0.001). The 2MACE score was positively associated with an increase in the risk of MACE, with a score of ≥ 2 providing the best combination of sensitivity (69.6%) and specificity (51.6%), HR 2.47 (95% CI, 2.21-2.77). The 2MACE score had modest predictive performance for MACE in patients with AF (AUC 0.655 (95% CI, 0.641-0.669)). Our analysis in this prospective global registry demonstrates that the 2MACE score can adequately predict the risk of MACE (defined as myocardial infarction, CV death and stroke) in patients with AF. Clinical trial registration: http://www.clinicaltrials.gov . Unique identifiers: NCT01468701, NCT01671007 and NCT01937377

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

DSL-Notch Signaling in the Drosophila Brain in Response to Olfactory Stimulation

SummaryDelta/Serrate/Lag2 (DSL) ligands and their Notch family receptors have profound and pervasive roles in development. They are also expressed in adult tissues, notably in mature neurons and glia in the brain, where their roles are unknown. Here, focusing on the sense of smell in adult Drosophila, we show that Notch is activated in select olfactory receptor neurons (ORNs) in an odorant-specific fashion. This response requires olfactory receptor activity and the Notch ligand Delta. We present evidence that Notch activation depends on synaptic transmission by the ORNs in which the receptors are active and is modulated by the activity of local interneurons in the antennal lobe. It is also subject to regulatory inputs from olfactory receptor activity in other ORNs. These findings identify a correlate of stimulus-dependent brain activity and potentially new forms of neural integration and plasticity

kuzbanian-mediated cleavage of Drosophila Notch

Loss of Kuzbanian, a member of the ADAM family of metalloproteases, produces neurogenic phenotypes in Drosophila. It has been suggested that this results from a requirement for kuzbanian-mediated cleavage of the Notch ligand Delta. Using transgenic Drosophila expressing transmembrane Notch proteins, we show that kuzbanian, independent of any role in Delta processing, is required for the cleavage of Notch. We show that Kuzbanian can physically associate with Notch and that removal of kuzbanian activity by RNA-mediated interference in Drosophila tissue culture cells eliminates processing of ligand-independent transmembrane Notch molecules. Our data suggest that in Drosophila, kuzbanian can mediate S2 cleavage of Notch