In neural systems, information is often carried by ensembles of cells rather than by individual units. Optical indicators provide a powerful means to reveal such distributed activity, particularly ...when protein-based and encodable in DNA: encodable probes can be introduced into cells, tissues, or transgenic organisms by genetic manipulation, selectively expressed in anatomically or functionally defined groups of cells, and, ideally, recorded in situ, without a requirement for exogenous cofactors. Here we describe sensors for secretion and neurotransmission that fulfil these criteria. We have developed pH-sensitive mutants of green fluorescent protein ('pHluorins') by structure-directed combinatorial mutagenesis, with the aim of exploiting the acidic pH inside secretory vesicles, to monitor vesicle exocytosis and recycling. When linked to a vesicle membrane protein, pHluorins were sorted to secretory and synaptic vesicles and reported transmission at individual synaptic boutons, as well as secretion and fusion pore 'flicker' of single secretory granules.
We have conducted a detailed investigation of the broadband spectral properties of the gamma-ray selected blazars of the Fermi LAT Bright AGN Sample (LBAS). By combining our accurately estimated ...Fermi gamma-ray spectra with Swift, radio, infra-red, optical, and other hard X-ray/gamma-ray data, collected within 3 months of the LBAS data taking period, we were able to assemble high-quality and quasi-simultaneous spectral energy distributions (SED) for 48 LBAS blazars. The SED of these gamma-ray sources is similar to that of blazars discovered at other wavelengths, clearly showing, in the usual log nu-log nu F-nu representation, the typical broadband spectral signatures normally attributed to a combination of low-energy synchrotron radiation followed by inverse Compton emission of one or more components. We have used these SED to characterize the peak intensity of both the low-and the high-energy components. The results have been used to derive empirical relationships that estimate the position of the two peaks from the broadband colors (i.e., the radio to optical, alpha(ro), and optical to X-ray, alpha(ox), spectral slopes) and from the gamma-ray spectral index. Our data show that the synchrotron peak frequency (nu(S)(peak)) is positioned between 10(12.5) and 10(14.5) Hz in broad-lined flat spectrum radio quasars (FSRQs) and between 10(13) and 10(17) Hz in featureless BL Lacertae objects. We find that the gamma-ray spectral slope is strongly correlated with the synchrotron peak energy and with the X-ray spectral index, as expected at first order in synchrotron-inverse Compton scenarios. However, simple homogeneous, one-zone, synchrotron self-Compton (SSC) models cannot explain most of our SED, especially in the case of FSRQs and low energy peaked (LBL) BL Lacs. More complex models involving external Compton radiation or multiple SSC components are required to reproduce the overall SED and the observed spectral variability. While more than 50% of known radio bright high energy peaked (HBL) BL Lacs are detected in the LBAS sample, only less than 13% of known bright FSRQs and LBL BL Lacs are included. This suggests that the latter sources, as a class, may be much fainter gamma-ray emitters than LBAS blazars, and could in fact radiate close to the expectations of simple SSC models. We categorized all our sources according to a new physical classification scheme based on the generally accepted paradigm for Active Galactic Nuclei and on the results of this SED study. Since the LAT detector is more sensitive to flat spectrum gamma-ray sources, the correlation between nu(S)(peak) and gamma-ray spectral index strongly favors the detection of high energy peaked blazars, thus explaining the Fermi overabundance of this type of sources compared to radio and EGRET samples. This selection effect is similar to that experienced in the soft X-ray band where HBL BL Lacs are the dominant type of blazars.
Abstract
Extreme high-frequency-peaked BL Lac objects (EHBLs) are blazars that exhibit extremely energetic synchrotron emission. They also feature nonthermal gamma-ray emission whose peak lies in the ...very high-energy (VHE,
E
> 100 GeV) range, and in some sources exceeds 1 TeV: this is the case for hard-TeV EHBLs such as 1ES 0229+200. With the aim of increasing the EHBL population, 10 targets were observed with the MAGIC telescopes from 2010 to 2017, for a total of 265 hr of good-quality data. The data were complemented by coordinated
Swift
observations. The X-ray data analysis confirms that all but two sources are EHBLs. The sources show only a modest variability and a harder-when-brighter behavior, typical for this class of objects. At VHE gamma-rays, three new sources were detected and a hint of a signal was found for another new source. In each case, the intrinsic spectrum is compatible with the hypothesis of a hard-TeV nature of these EHBLs. The broadband spectral energy distributions (SEDs) of all sources are built and modeled in the framework of a single-zone, purely leptonic model. The VHE gamma-ray-detected sources were also interpreted with a spine–layer model and a proton synchrotron model. The three models provide a good description of the SEDs. However, the resulting parameters differ substantially in the three scenarios, in particular the magnetization parameter. This work presents the first mini catalog of VHE gamma-ray and multiwavelength observations of EHBLs.
Introduction: Our objective is to highlight the value of the neurophenomenological classification of complex visual hallucinations (VHs). This approach enabled the authors to successfully treat VHs ...of uncertain aetiology with cholinesterase inhibitors because the content of the hallucinations suggested dysfunction in cholinergic modulated networks.
Methods: We utilise the single case report to describe the nature and content of chronic VHs experienced by a 49-year-old woman following a prolonged admission to ITU. Despite extensive investigation, no clear cause was identified for these hallucinations and the patient did not respond to rationalisation of medications or trials of antipsychotics. We therefore adopted the neurophenomenological approach to classifying and treating her VHs.
Results: After several years of distressing visual hallucinations, a course of Rivastigmine was trialed despite no evidence suggestive of a Parkinsonian syndrome. Nevertheless, the patient reported a dose-effect response with significant reduction in the frequency and intensity of her hallucinations, almost to complete resolution.
Conclusions: At present there is limited evidence about the medical management of visual hallucinations. This case report suggests that cholinesterase inhibitors may be of benefit, even in the absence of clear parkinsonsian features, if the form and content of the VHs suggest dysfunction in cholinergic modulated attentional networks.
Background and purpose
Hypomimia is a prominent clinical feature in people with Parkinson’s disease (PD), but it remains under‐investigated. We aimed to examine the clinical correlates of hypomimia ...in PD and to determine whether this is a levodopa‐responsive sign.
Methods
We included 89 people with PD. Hypomimia was assessed from digital video recordings by movement disorder specialists. Clinical evaluation included use of the Unified Parkinson’s Disease Rating Scale part III (UPDRS‐III), and assessment of motor and non‐motor symptoms using standardized clinical scales. The relationships between hypomimia and other clinical data were analysed using Mann–Whitney U‐tests and regression analysis.
Results
Hypomimia occurred in up to 70% of patients with PD. Patients with hypomimia had worse UPDRS‐III 'off‐medication' scores, mainly driven by bradykinesia and rigidity subscores. Patients with hypomimia also had worse apathy than patients without hypomimia. Finally, we found that hypomimia was levodopa‐responsive and its improvement mirrored the change by levodopa in axial motor symptoms.
Conclusion
Our study provides novel information regarding the clinical correlates of hypomimia in people with PD. A better understanding of hypomimia may be relevant for improving treatment and quality of life in PD.
Abstract It is commonly accepted that the renin-angiotensin-aldosterone system (RAAS) is a cardiovascular circulating hormonal system that plays also an important role in the modulation of several ...patterns in the brain. The pathway of the RAAS can be divided into two classes: the traditional pathway of RAAS, also named classic RAAS, and the non-classic RAAS. Both pathways play a role in both cardiovascular and neurological diseases through a peripheral or central control. In this regard, renewed interest is growing in the last years for the consideration that the brain RAAS could represent a new important therapeutic target to regulate not only the blood pressure via central nervous control, but also neurological diseases. However, the development of compounds able to cross the blood–brain barrier and to act on the brain RAAS is challenging, especially if the metabolic stability and the half-life are taken into consideration. To date, two drug classes (aminopeptidase type A inhibitors and angiotensin IV analogues) acting on the brain RAAS are in development in pre-clinical or clinical stages. In this article, we will present an overview of the biological functions played by peripheral and brain classic and non-classic pathways of the RAAS in several clinical conditions, focusing on the brain RAAS and on the new pharmacological targets of the RAAS.
Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with substantial morbidity and mortality. Pathophysiological aspects consist in the activation of pro-fibrotic signaling and ...Ca2+ handling abnormalities at atrial level. Structural and electrical remodeling creates a substrate for AF by triggering conduction abnormalities and cardiac arrhythmias. The care of AF patients focuses predominantly on anticoagulation, symptoms control and the management of risk factors and comorbidities. The goal of AF therapy points to restore sinus rhythm, re-establish atrioventricular synchrony and improve atrial contribution to the stroke volume. New layer of information to better comprehend AF pathophysiology, and identify targets for novel pharmacological interventions consists of the epigenetic phenomena including, among others, DNA methylation, histone modifications and noncoding RNAs. Moreover, the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in diabetic and non-diabetic patients at cardiovascular risk as well as emerging evidence on the ability of SGLT2i to modify epigenetic signature in cardiovascular diseases provide a solid background to investigate a possible role of this drug class in the onset and progression of AF.
In this review, following a summary of pathophysiology and management, epigenetic mechanisms in AF and the potential of sodium-glucose SGLT2i in AF patients are discussed.
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The origin of Galactic cosmic rays is a century-long puzzle. Indirect evidence points to their acceleration by supernova Shockwaves, but we know little of their escape from the shock and their ...evolution through the turbulent medium surrounding massive stars. Gamma rays can probe their spreading through the ambient gas and radiation fields. The Fermi Large Area Telescope (LAT) has observed the star-forming region of Cygnus X. The 1-to 100-gigaelectronvolt images reveal a 50-parsec-wide cocoon of freshly accelerated cosmic rays that flood the cavities carved by the stellar winds and ionization fronts from young stellar clusters. It provides an example to study the youth of cosmic rays in a superbubble environment before they merge into the older Galactic population.
We report on the Delta *g-ray activity of the high-synchrotron-peaked BL Lacertae object Markarian 421 (Mrk 421) during the first 1.5 years of Fermi operation, from 2008 August 5 to 2010 March 12. We ...find that the Large Area Telescope (LAT) Delta *g-ray spectrum above 0.3 GeV can be well described by a power-law function with photon index Delta *G = 1.78 ? 0.02 and average photon flux F(> 0.3 GeV) = (7.23 ? 0.16) X 10--8 ph cm--2 s--1. Over this time period, the Fermi-LAT spectrum above 0.3 GeV was evaluated on seven-day-long time intervals, showing significant variations in the photon flux (up to a factor ~3 from the minimum to the maximum flux) but mild spectral variations. The variability amplitude at X-ray frequencies measured by RXTE/ASM and Swift/BAT is substantially larger than that in Delta *g-rays measured by Fermi-LAT, and these two energy ranges are not significantly correlated. We also present the first results from the 4.5 month long multifrequency campaign on Mrk 421, which included the VLBA, Swift, RXTE, MAGIC, the F-GAMMA, GASP-WEBT, and other collaborations and instruments that provided excellent temporal and energy coverage of the source throughout the entire campaign (2009 January 19 to 2009 June 1). During this campaign, Mrk 421 showed a low activity at all wavebands. The extensive multi-instrument (radio to TeV) data set provides an unprecedented, complete look at the quiescent spectral energy distribution (SED) for this source. The broadband SED was reproduced with a leptonic (one-zone synchrotron self-Compton) and a hadronic model (synchrotron proton blazar). Both frameworks are able to describe the average SED reasonably well, implying comparable jet powers but very different characteristics for the blazar emission site.
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