Molecular Determinants of Agonist Discrimination by NMDA Receptor Subunits: Analysis of the Glutamate Binding Site on the NR2B Subunit

AbstractNMDA receptors require both L-glutamate and the coagonist glycine for efficient channel activation. The glycine binding site of these heteromeric receptor proteins is formed by regions of the NMDAR1 (NR1) subunit that display sequence similarity to bacterial amino acid binding proteins. Here, we demonstrate that the glutamate binding site is located on the homologous regions of the NR2B subunit. Mutation of residues within the N-terminal domain and the loop region between membrane segments M3 and M4 significantly reduced the efficacy of glutamate, but not glycine, in channel gating. Some of the mutations also decreased inhibition by the glutamate antagonists, D-AP5 and R-CPP. Homology-based molecular modeling of the glutamate and glycine binding domains indicates that the NR2 and NR1 subunits use similar residues to ligate the agonists' α-aminocarboxylic acid groups, whereas differences in side chain interactions and size of aromatic residues determine ligand selectivity

Prehomogeneous Super Vector Spaces

In this thesis, we develop the theory of prehomogeneous super vector spaces. In the case that $G$ is a complex connected Lie supergroup, acting linearly on a super vector space $V$ and if $G$ has an open orbit in $V$ then this orbit, as an open sub supermanifold, is unique, connected and dense. This allows us to define prehomogeneous super vector spaces. We introduce the notion of relative superinvariants and show that the relative superinvariants are already determined by the supercharacters which are invariant under the isotropy supergroup. Furthermore, we construct two examples of prehomogeneous super vector spaces. The supercharacters of the general linear supergroup will be classified and thereby all relative superinvariants for the space of supersymmetric matrices. We introduce the local zeta superfunction for the prehomogeneous super vector space of supersymmetric matrices and prove that these are entire functions. Moreover, for a compactly supported superfunction $\Phi_c$ on a connected component $V_{ij}$ of the orbit the local zeta superfunction $$F_{ij}(s,\Phi_{c})=\frac{1}{\gamma(s)}\int_{V_{ij}} |D(X)|\ |\mathrm{Ber}(X)|^s\ \Phi_{c}(X),\\$$ is a regularization of the integral on the right-hand side to the greater space of Schwartz superfunctions. These are defined on the associated $cs$-vector space. Unlike the regularization methods of Marcel Riesz and Hadamard, where homogeneous distributions lose their homogeneity, this regularization method, already used by Gelfand and Sato, maintains the algebraic property of relative superinvariant. Moreover, we demonstrate that the Fourier supertransform is, up to a supercharacter, an equivariant map for the induced action on the super vector space of Schwartz superfunctions. We also prove that the Fourier supertransform of the dual local zeta superfunctions transforms with the same supercharacter as the local zeta superfunction, shifted in the complex parameter

Short-term effects of air pollution: a panel study of blood markers in patients with chronic pulmonary disease

<p>Abstract</p> <p>Background</p> <p>Growing evidence indicates that ambient air pollution is associated with exacerbation of chronic diseases like chronic pulmonary disease. A prospective panel study was conducted to investigate short-term changes of blood markers of inflammation and coagulation in response to daily changes in air pollution in Erfurt, Germany. 12 clinical visits were scheduled and blood parameters were measured in 38 male patients with chronic pulmonary disease during winter 2001/2002. Additive mixed models with random patient intercept were applied, adjusting for trend, weekday, and meteorological parameters. Hourly data on ultrafine particles (UFP, 0.01-0.1 μm), accumulation mode particles (ACP, 0.1-1.0 μm), PM₁₀(particulate matter <10 μm in diameter), elemental (EC) and organic carbon (OC), gaseous pollutants (nitrogen monoxide [NO], nitrogen dioxide [NO₂], carbon monoxide [CO], and sulphur dioxide [SO₂]) were collected at a central monitoring site and meteorological data were received from an official network. For each person and visit the individual 24-hour average of pollutants immediately preceding the blood withdrawal (lag 0) up to day 5 (lag1-4) and 5-day running means were calculated.</p> <p>Results</p> <p>Increased levels of fibrinogen were observed for an increase in one interquartile range of UFP, PM₁₀, EC, OC, CO, and NO revealing the strongest effect for lag 3. E-selectin increased in association with ACP and PM₁₀with a delay of one day. The ACP effect was also seen with the 5-day-mean. The pattern found for D-dimer was inconsistent. Prothrombin fragment 1+2 decreased with lag 4 consistently for all particulate pollutants. Von Willebrand factor antigen (vWF) showed a consistent decrease in association with almost all air pollutants with all lags except for lag 0. No associations were found for C-reactive protein, soluble intercellular adhesion molecule 1, serum amyloid A and factor VII.</p> <p>Conclusion</p> <p>These results suggest that elevated concentrations of air pollution are associated with changes in some blood markers of inflammation and coagulation in patients with chronic pulmonary disease. The clinical implications of these findings need further investigation.</p

Retrieval-Augmented Generation for Knowledge-Intensive NLP Tasks

Large pre-trained language models have been shown to store factual knowledge in their parameters, and achieve state-of-the-art results when fine-tuned on downstream NLP tasks. However, their ability to access and precisely manipulate knowledge is still limited, and hence on knowledge-intensive tasks, their performance lags behind task-specific architectures. Additionally, providing provenance for their decisions and updating their world knowledge remain open research problems. Pre-trained models with a differentiable access mechanism to explicit non-parametric memory can overcome this issue, but have so far been only investigated for extractive downstream tasks. We explore a general-purpose fine-tuning recipe for retrieval-augmented generation (RAG) -- models which combine pre-trained parametric and non-parametric memory for language generation. We introduce RAG models where the parametric memory is a pre-trained seq2seq model and the non-parametric memory is a dense vector index of Wikipedia, accessed with a pre-trained neural retriever. We compare two RAG formulations, one which conditions on the same retrieved passages across the whole generated sequence, the other can use different passages per token. We fine-tune and evaluate our models on a wide range of knowledge-intensive NLP tasks and set the state-of-the-art on three open domain QA tasks, outperforming parametric seq2seq models and task-specific retrieve-and-extract architectures. For language generation tasks, we find that RAG models generate more specific, diverse and factual language than a state-of-the-art parametric-only seq2seq baseline.Comment: Accepted at NeurIPS 202

myCopter: Enabling Technologies for Personal Air Transport Systems

This paper describes the European Commission Framework 7 funded project myCopter (2011-2014). The project is still at an early stage so the paper starts with the current transportation issues faced by developed countries and describes a means to solve them through the use of personal aerial transportation. The concept of personal air vehicles (PAV) is briefly reviewed and how this project intends to tackle the problem from a different perspective described. It is argued that the key reason that many PAV concepts have failed is because the operational infrastructure and socio-economic issues have not been properly addressed; rather, the start point has been the design of the vehicle itself. Some of the key aspects that would make a personal aerial transport system (PATS) viable include the required infrastructure and associated technologies, the skill levels and machine interfaces needed by the occupant or pilot and the views of society as a whole on the acceptability of such a proposition. The myCopter project will use these areas to explore the viability of PAVs within a PATS. The paper provides an overview of the project structure, the roles of the partners, and hence the available research resources, and some of the early thinking on each of the key project topic areas

Nemszinaptikus transmisszió: egy új megközelítés az alapvető agy funkciók megértéséhez = Nonsynaptic transmission: a new pathway to understand major brain functions

A két-foton mikroszkópia használata új információkat szolgáltatott a nemszinaptikus kölcsönhatásokról szubmikronos anatómiai struktúrákban. Feltérképeztük a technika felhasználásának lehetőségeit a különböző szövetpreparátumok, idegsejttípusok esetében. A membrán Na+/Ca2+ cserélő gátlása elsősorban a dendrittörzsben befolyásolja a szinaptikus Ca2+ tranzienseket, és szabályozza a tüske-dendrit kapcsolatot. A dendritikus Ca2+ válaszok szintjén a noradrenalin pozitív hatású a dendritikus integráció kapacitásaira nézve, elősegíti a dendritikus potenciálok keletkezését, előnyös a munkamemóriára nézve. Kísérleteink feltárták a nikotin sokrétű serkentő hatásait a dendritek funkcióira nézve, így az akciós potenciálok terjedésének erősítését, spontán válaszok kialakulását a piramissejtek tüskéiben, illetve az interneuronok dendrittörzsében. A farmakológiai alkalmazások közül az antidepresszánsok hatásait vizsgáltuk. Elképzelhető, hogy az antidepresszánsok a lassú inaktivált állapot stabilizálásának keresztül gátolják a Na+ csatorna funkciót úgy, hogy segítsék a depressziós neurális "körök" oldódását. A terápia során kialakuló koncentráció viszonyokban a fluoxetin és a dezipramin az NMDA receptorok működését hatékonyan gátolhatják, ami fontos eleme lehet a depresszió oldásának. | The use of two-photon microscopy yielded novel information about the nonsynaptic interactions in submicron anatomical structures. We mapped the applicational possibilities of this technique using various tissue preparations and neuron types. The inhibition of the membrane Na+/Ca2+ exchanger primarily influenced the synaptic Ca2+ transients in the dendrite shaft and regulate locally the dendrite/spine connectivity. At the level of the dendritic Ca2+ responses, noradrenaline has a positive effect on the capacity of dendritic integration, promotes the initiation of dendritic spikes, and enhances working memory. Our experiments revealed that nicotine has multiple effects on dendritic functions including the strengthening the propagation of action potentials in the dendrite and inducing spontaneous responses in dendritic spines of the pyramidal neurons and dendrites of interneurons. Among the pharmacological applications, we studied the effects of antidepressants. It is possible that the antidepressants block the function of the Na+ channel through the stabilization of the inactivated state in a way that helps unbound the depressive "circuits". At therapeutically relevant concentrations fluoxetine and desipramine can efficiently inhibit the function of the NMDA receptor that might be an important element of antidepressive mechanisms

CAST constraints on the axion-electron coupling

In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission

ERIS: revitalising an adaptive optics instrument for the VLT

ERIS is an instrument that will both extend and enhance the fundamental diffraction limited imaging and spectroscopy capability for the VLT. It will replace two instruments that are now being maintained beyond their operational lifetimes, combine their functionality on a single focus, provide a new wavefront sensing module that makes use of the facility Adaptive Optics System, and considerably improve their performance. The instrument will be competitive with respect to JWST in several regimes, and has outstanding potential for studies of the Galactic Center, exoplanets, and high redshift galaxies. ERIS had its final design review in 2017, and is expected to be on sky in 2020. This contribution describes the instrument concept, outlines its expected performance, and highlights where it will most excel.Comment: 12 pages, Proc SPIE 10702 "Ground-Based and Airborne Instrumentation for Astronomy VII

The P3^3 Experiment: A Positron Source Demonstrator for Future Lepton Colliders

The PSI Positron Production (P$^3$ or P-cubed) experiment is a demonstrator for a e+ source and capture system with potential to improve the state-of-the-art e+ yield by an order of magnitude. The experiment is driven by the FCC-ee injector study and will be hosted in the SwissFEL facility at the Paul Scherrer Institute in Switzerland. This paper is an overview of the P$^3$ design at an advanced stage, with a particular emphasis on a novel e+ capture system and its associated beam dynamics. Additionally, a concept for the experiment diagnostics is presented, as well as the key points of the ongoing installation works