Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid

Caspase-8 is involved in death receptor-mediated apoptosis in type II cells, the proapoptotic programme of which is triggered by truncated Bid. Indeed, caspase-8 and Bid are the known intermediates of this signalling pathway. Cardiolipin has been shown to provide an anchor and an essential activating platform for caspase-8 at the mitochondrial membrane surface. Destabilisation of this platform alters receptor-mediated apoptosis in diseases such as Barth Syndrome, which is characterised by the presence of immature cardiolipin which does not allow caspase-8 binding. We used a simplified in vitro system that mimics contact sites and/or cardiolipin-enriched microdomains at the outer mitochondrial surface in which the platform consisting of caspase-8, Bid and cardiolipin was reconstituted in giant unilamellar vesicles. We analysed these vesicles by flow cytometry and confirm previous results that demonstrate the requirement for intact mature cardiolipin for caspase-8 activation and Bid binding and cleavage. We also used confocal microscopy to visualise the rupture of the vesicles and their revesiculation at smaller sizes due to alteration of the curvature following caspase-8 and Bid binding. Biophysical approaches, including Laurdan fluorescence and rupture/tension measurements, were used to determine the ability of these three components (cardiolipin, caspase-8 and Bid) to fulfil the minimal requirements for the formation and function of the platform at the mitochondrial membrane. Our results shed light on the active functional role of cardiolipin, bridging the gap between death receptors and mitochondria

Toxoplasma Effector MAF1 Mediates Recruitment of Host Mitochondria and Impacts the Host Response

Recent information has revealed the functional diversity and importance of mitochondria in many cellular processes including orchestrating the innate immune response. Intriguingly, several infectious agents, such as Toxoplasma, Legionella, and Chlamydia, have been reported to grow within vacuoles surrounded by host mitochondria. Although many hypotheses have been proposed for the existence of host mitochondrial association (HMA), the causes and biological consequences of HMA have remained unanswered. Here we show that HMA is present in type I and III strains of Toxoplasma but missing in type II strains, both in vitro and in vivo. Analysis of F1 progeny from a type II×III cross revealed that HMA is a Mendelian trait that we could map. We use bioinformatics to select potential candidates and experimentally identify the polymorphic parasite protein involved, mitochondrial association factor 1 (MAF1). We show that introducing the type I (HMA+) MAF1 allele into type II (HMA-) parasites results in conversion to HMA+ and deletion of MAF1 in type I parasites results in a loss of HMA. We observe that the loss and gain of HMA are associated with alterations in the transcription of host cell immune genes and the in vivo cytokine response during murine infection. Lastly, we use exogenous expression of MAF1 to show that it binds host mitochondria and thus MAF1 is the parasite protein directly responsible for HMA. Our findings suggest that association with host mitochondria may represent a novel means by which Toxoplasma tachyzoites manipulate the host. The existence of naturally occurring HMA+ and HMA- strains of Toxoplasma, Legionella, and Chlamydia indicates the existence of evolutionary niches where HMA is either advantageous or disadvantageous, likely reflecting tradeoffs in metabolism, immune regulation, and other functions of mitochondria. © 2014 Pernas et al

On the Nonlinearity of Modern Shock-Capturing Schemes

The development is reviewed of shock capturing methods, paying special attention to the increasing nonlinearity in the design of numerical schemes. The nature is studies of this nonlinearity and its relation to upwind differencing is examined. This nonlinearity of the modern shock capturing methods is essential, in the sense that linear analysis is not justified and may lead to wrong conclusions. Examples to demonstrate this point are given

13C-direct detected NMR experiments for the sequential J-based resonance assignment of RNA oligonucleotides

We present here a set of 13C-direct detected NMR experiments to facilitate the resonance assignment of RNA oligonucleotides. Three experiments have been developed: (1) the (H)CC-TOCSY-experiment utilizing a virtual decoupling scheme to assign the intraresidual ribose 13C-spins, (2) the (H)CPC-experiment that correlates each phosphorus with the C4′ nuclei of adjacent nucleotides via J(C,P) couplings and (3) the (H)CPC-CCH-TOCSY-experiment that correlates the phosphorus nuclei with the respective C1′,H1′ ribose signals. The experiments were applied to two RNA hairpin structures. The current set of 13C-direct detected experiments allows direct and unambiguous assignment of the majority of the hetero nuclei and the identification of the individual ribose moieties following their sequential assignment. Thus, 13C-direct detected NMR methods constitute useful complements to the conventional 1H-detected approach for the resonance assignment of oligonucleotides that is often hindered by the limited chemical shift dispersion. The developed methods can also be applied to large deuterated RNAs

Classification of Ventricular Septal Defects for the Eleventh Iteration of the International Classification of Diseases—Striving for Consensus: A Report From the International Society for Nomenclature of Paediatric and Congenital Heart Disease

The definition and classification of ventricular septal defects have been fraught with controversy. The International Society for Nomenclature of Paediatric and Congenital Heart Disease is a group of international specialists in pediatric cardiology, cardiac surgery, cardiac morphology, and cardiac pathology that has met annually for the past 9 years in an effort to unify by consensus the divergent approaches to describe ventricular septal defects. These efforts have culminated in acceptance of the classification system by the World Health Organization into the 11th Iteration of the International Classification of Diseases. The scheme to categorize a ventricular septal defect uses both its location and the structures along its borders, thereby bridging the two most popular and disparate classification approaches and providing a common language for describing each phenotype. Although the first-order terms are based on the geographic categories of central perimembranous, inlet, trabecular muscular, and outlet defects, inlet and outlet defects are further characterized by descriptors that incorporate the borders of the defect, namely the perimembranous, muscular, and juxta-arterial types. The Society recognizes that it is equally valid to classify these defects by geography or borders, so the emphasis in this system is on the second-order terms that incorporate both geography and borders to describe each phenotype. The unified terminology should help the medical community describe with better precision all types of ventricular septal defects

Orbital reflectometry

The occupation of d-orbitals controls the magnitude and anisotropy of the inter-atomic electron transfer in transition metal oxides and hence exerts a key influence on their chemical bonding and physical properties. Atomic-scale modulations of the orbital occupation at surfaces and interfaces are believed to be responsible for massive variations of the magnetic and transport properties, but could thus far not be probed in a quantitative manner. Here we show that it is possible to derive quantitative, spatially resolved orbital polarization profiles from soft x-ray reflectivity data, without resorting to model calculations. We demonstrate that the method is sensitive enough to resolve differences of 3 % in the occupation of Ni e_g orbitals in adjacent atomic layers of a LaNiO3-LaAlO3 superlattice, in good agreement with ab-initio electronic-structure calculations. The possibility to quantitatively correlate theory and experiment on the atomic scale opens up many new perspectives for orbital physics in d-electron materials

Nomenclature for Pediatric and Congenital Cardiac Care: Unification of Clinical and Administrative Nomenclature – The 2021 International Paediatric and Congenital Cardiac Code (IPCCC) and the Eleventh Revision of the International Classification of Diseases (ICD-11)

Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code ( IPCCC ) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases ( ICD-11 ). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC . The International Society for Nomenclature of Paediatric and Congenital Heart Disease ( ISNPCHD ), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature . This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature. The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC , as IPCCC continues to evolve

Evaluation of fast atmospheric dispersion models in a regular street network

The need to balance computational speed and simulation accuracy is a key challenge in designing atmospheric dispersion models that can be used in scenarios where near real-time hazard predictions are needed. This challenge is aggravated in cities, where models need to have some degree of building-awareness, alongside the ability to capture effects of dominant urban flow processes. We use a combination of high-resolution large-eddy simulation (LES) and wind-tunnel data of flow and dispersion in an idealised, equal-height urban canopy to highlight important dispersion processes and evaluate how these are reproduced by representatives of the most prevalent modelling approaches: (i) a Gaussian plume model, (ii) a Lagrangian stochastic model and (iii) street-network dispersion models. Concentration data from the LES, validated against the wind-tunnel data, were averaged over the volumes of streets in order to provide a high-fidelity reference suitable for evaluating the different models on the same footing. For the particular combination of forcing wind direction and source location studied here, the strongest deviations from the LES reference were associated with mean over-predictions of concentrations by approximately a factor of 2 and with a relative scatter larger than a factor of 4 of the mean, corresponding to cases where the mean plume centreline also deviated significantly from the LES. This was linked to low accuracy of the underlying flow models/parameters that resulted in a misrepresentation of pollutant channelling along streets and of the uneven plume branching observed in intersections. The agreement of model predictions with the LES (which explicitly resolves the turbulent flow and dispersion processes) greatly improved by increasing the accuracy of building-induced modifications of the driving flow field. When provided with a limited set of representative velocity parameters, the comparatively simple street-network models performed equally well or better compared to the Lagrangian model run on full 3D wind fields. The study showed that street-network models capture the dominant building-induced dispersion processes in the canopy layer through parametrisations of horizontal advection and vertical exchange processes at scales of practical interest. At the same time, computational costs and computing times associated with the network approach are ideally suited for emergency-response applications