Role of LGI1 protein in synaptic transmission: From physiology to pathology

Leucine-Rich Glioma Inactivated protein 1 (LGI1) is a secreted neuronal protein highly expressed in the central nervous system and high amount are found in the hippocampus. An alteration of its function has been described in few families of patients with autosomal dominant temporal lobe epilepsy (ADLTE) or with autoimmune limbic encephalitis (LE), both characterized by epileptic seizures. Studies have shown that LGI1 plays an essential role during development, but also in neuronal excitability through an action on voltage-gated potassium Kv1.1 channels, and in synaptic transmission by regulating the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R). Over the last decade, a growing number of studies investigating LGI1 functions have been published. They aimed to improve the understanding of LGI1 function in the regulation of neuronal networks using different animal and cellular models. LGI1 appears to be a major actor of synaptic regulation by modulating trans-synaptically pre- and post-synaptic proteins. In this review, we will focus on LGI1 binding partners, “A Disintegrin And Metalloprotease (ADAM) 22 and 23”, the complex they form at the synapse, and will discuss the effects of LGI1 on neuronal excitability and synaptic transmission in physiological and pathological conditions. Finally, we will highlight new insights regarding N-terminal Leucine-Rich Repeat (LRR) domain and C-terminal Epitempin repeat (EPTP) domain and their potentially distinct role in LGI1 function

On post-Lie algebras, Lie--Butcher series and moving frames

Pre-Lie (or Vinberg) algebras arise from flat and torsion-free connections on differential manifolds. They have been studied extensively in recent years, both from algebraic operadic points of view and through numerous applications in numerical analysis, control theory, stochastic differential equations and renormalization. Butcher series are formal power series founded on pre-Lie algebras, used in numerical analysis to study geometric properties of flows on euclidean spaces. Motivated by the analysis of flows on manifolds and homogeneous spaces, we investigate algebras arising from flat connections with constant torsion, leading to the definition of post-Lie algebras, a generalization of pre-Lie algebras. Whereas pre-Lie algebras are intimately associated with euclidean geometry, post-Lie algebras occur naturally in the differential geometry of homogeneous spaces, and are also closely related to Cartan's method of moving frames. Lie--Butcher series combine Butcher series with Lie series and are used to analyze flows on manifolds. In this paper we show that Lie--Butcher series are founded on post-Lie algebras. The functorial relations between post-Lie algebras and their enveloping algebras, called D-algebras, are explored. Furthermore, we develop new formulas for computations in free post-Lie algebras and D-algebras, based on recursions in a magma, and we show that Lie--Butcher series are related to invariants of curves described by moving frames.Comment: added discussion of post-Lie algebroid

Semiclassical States in Quantum Cosmology: Bianchi I Coherent States

We study coherent states for Bianchi type I cosmological models, as examples of semiclassical states for time-reparametrization invariant systems. This simple model allows us to study explicitly the relationship between exact semiclassical states in the kinematical Hilbert space and corresponding ones in the physical Hilbert space, which we construct here using the group averaging technique. We find that it is possible to construct good semiclassical physical states by such a procedure in this model; we also discuss the sense in which the original kinematical states may be a good approximation to the physical ones, and the situations in which this is the case. In addition, these models can be deparametrized in a natural way, and we study the effect of time evolution on an "intrinsic" coherent state in the reduced phase space, in order to estimate the time for this state to spread significantly.Comment: 21 pages, 1 figure; Version to be published in CQG; The discussion has been slightly reorganized, two references added, and some typos correcte

Comments on "Economic policy for the European Community - the way forward". Selection of comments prepared for a Kiel Symposium on the report of the Group of Rome

Table of Contents: Herbert Giersch, Gottfried Haberler, Jan Tumlir, Juergen B. Donges, Bela Balassa, Europe's Role in the World Economy; Fritz Machlup, Johann Schollhorn, Norbert Walter Pascal Salin, Roland Vaubel, Roads to Monetary Union; Willi Albers, Fritz Neumark, Carl S. Shoup, Dieter Biehl, Fiscal Harmonization; Dieter Biehl, Bela Balassa, Claus Noe, Sebastian Schnyder, The Scope of a Common Regional Policy; Adolf Weber, Tim Josling, New Approaches to Structural Policy? Reforming the Common Agricultural Policy; Gerhard Prosi, Gerhard Fels, Klaus Stegemann, New Approaches to Structural Policy? Industrial Policy, Competition and Social Progres

Explicit differential characterization of the Newtonian free particle system in m > 1 dependent variables

In 1883, as an early result, Sophus Lie established an explicit necessary and sufficient condition for an analytic second order ordinary differential equation y_xx = F(x,y,y_x) to be equivalent, through a point transformation (x,y) --> (X(x,y), Y(x,y)), to the Newtonian free particle equation Y_XX = 0. This result, preliminary to the deep group-theoretic classification of second order analytic ordinary differential equations, was parachieved later in 1896 by Arthur Tresse, a French student of S. Lie. In the present paper, following closely the original strategy of proof of S. Lie, which we firstly expose and restitute in length, we generalize this explicit characterization to the case of several second order ordinary differential equations. Let K=R or C, or more generally any field of characteristic zero equipped with a valuation, so that K-analytic functions make sense. Let x in K, let m > 1, let y := (y^1, ..., y^m) in K^m and let y_xx^j = F^j(x,y,y_x^l), j = 1,...,m be a collection of m analytic second order ordinary differential equations, in general nonlinear. We provide an explicit necessary and sufficient condition in order that this system is equivalent, under a point transformation (x, y^1, ..., y^m) --> (X(x,y), Y^1(x,y),..., Y^m(x, y)), to the Newtonian free particle system Y_XX^1 = ... = Y_XX^m = 0. Strikingly, the (complicated) differential system that we obtain is of first order in the case m > 1, whereas it is of second order in S. Lie's original case m = 1.Comment: 76 pages, no figur

A large ozone-circulation feedback and its implications for global warming assessments.

State-of-the-art climate models now include more climate processes which are simulated at higher spatial resolution than ever1. Nevertheless, some processes, such as atmospheric chemical feedbacks, are still computationally expensive and are often ignored in climate simulations1,2. Here we present evidence that how stratospheric ozone is represented in climate models can have a first order impact on estimates of effective climate sensitivity. Using a comprehensive atmosphere-ocean chemistry-climate model, we find an increase in global mean surface warming of around 1°C (~20%) after 75 years when ozone is prescribed at pre-industrial levels compared with when it is allowed to evolve self-consistently in response to an abrupt 4×CO2 forcing. The difference is primarily attributed to changes in longwave radiative feedbacks associated with circulation-driven decreases in tropical lower stratospheric ozone and related stratospheric water vapour and cirrus cloud changes. This has important implications for global model intercomparison studies1,2 in which participating models often use simplified treatments of atmospheric composition changes that are neither consistent with the specified greenhouse gas forcing scenario nor with the associated atmospheric circulation feedbacks3-5.We thank the European Research Council for funding through the ACCI project, project number 267760. The model development was part of the QESM-ESM project supported by the UK Natural Environment Research Council (NERC) under contract numbers RH/H10/19 and R8/H12/124. We acknowledge use of the MONSooN system, a collaborative facility supplied under the Joint Weather and Climate Research Programme, which is a strategic partnership between the UK Met Office and NERC. A.C.M. acknowledges support from an AXA Postdoctoral Research Fellowship.This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/nclimate/journal/v5/n1/full/nclimate2451.html

Hygienic quality of dehydrated aromatic herbs marketed in Southern Portugal

Dehydrated aromatic herbs are highly valued ingredients, widely used at home level and by food processing industry, frequently added to a great number of recipes in the Mediterranean countries. Despite being considered low-moisture products and classified as GRAS, during pre and post-harvesting stages of production they are susceptible of microbial contamination. In Europe an increasing number of food recalls and disease outbreaks associated with dehydrated herbs have been reported in recent years. In this study the microbial quality of 99 samples of aromatic herbs (bay leaves, basil, coriander, oregano, parsley, Provence herbs, rosemary and thyme) collected from retails shops in the region of Algarve (Southern Portugal) was assessed. All the samples were tested by conventional methods and were assayed for the total count of aerobic mesophilic microorganisms, Salmonella spp., Escherichia coli, coagulase-positive staphylococci and filamentous fungi. Almost 50 % of the herbs did not exceed the aerobic mesophilic level of 104 CFU/g. The fungi count regarded as unacceptable (106 CFU/g) was not found in any of the tested herbs, while 84 % of the samples ranged from ≤102 to 104 CFU/g. No sample was positive for the presence of Salmonella spp., Escherichia coli and staphylococci. The results are in compliance with the European Commission criteria although they point out to the permanent need of surveillance on the good standards of handling/cooking practices as well as the importance of avoiding contamination at production, retailing and distribution. The microbiological hazards associated with the pathogenic and toxigenic microbiota of dried herbs remain as a relevant public health issue, due to the fact that they are added to foods not submitted to any following lethal procedure. Control measures should be adopted in order to ensure that all phases of their supply chain respect the food safety standards.FCT: UID/BIA/04325/2019.info:eu-repo/semantics/publishedVersio

Alveolar macrophages regulate neutrophil recruitment in endotoxin-induced lung injury

BACKGROUND: Alveolar macrophages play an important role during the development of acute inflammatory lung injury. In the present study, in vivo alveolar macrophage depletion was performed by intratracheal application of dichloromethylene diphosphonate-liposomes in order to study the role of these effector cells in the early endotoxin-induced lung injury. METHODS: Lipopolysaccharide was applied intratracheally and the inflammatory reaction was assessed 4 hours later. Neutrophil accumulation and expression of inflammatory mediators were determined. To further analyze in vivo observations, in vitro experiments with alveolar epithelial cells and alveolar macrophages were performed. RESULTS: A 320% increase of polymorphonuclear leukocytes in bronchoalveolar lavage fluid was observed in macrophage-depleted compared to macrophage-competent lipopolysaccharide-animals. This neutrophil recruitment was also confirmed in the interstitial space. Monocyte chemoattractant protein-1 concentration in bronchoalveolar lavage fluid was significantly increased in the absence of alveolar macrophages. This phenomenon was underlined by in vitro experiments with alveolar epithelial cells and alveolar macrophages. Neutralizing monocyte chemoattractant protein-1 in the airways diminished neutrophil accumulation. CONCLUSION: These data suggest that alveolar macorphages play an important role in early endotoxin-induced lung injury. They prevent neutrophil influx by controlling monocyte chemoattractant protein-1 production through alveolar epithelial cells. Alveolar macrophages might therefore possess robust anti-inflammatory effects

Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy

We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (∼10 fold). It was also reported by others to have anti-tumor activity in vivo and selective toxicity against cancer cells under glucose starvation in vitro, but with unknown mechanism. Here, we provide evidence that pyrvinium suppresses the transcriptional activation of GRP78 and GRP94 induced by glucose deprivation or 2-deoxyglucose (2DG, a glycolysis inhibitor), but not by tunicamycin or A23187. Other UPR pathways induced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgene partially protected cells from pyrvinium induced cell death under glucose starvation, suggesting that suppression of the UPR is involved in pyrvinium mediated cytotoxicity under glucose starvation. Xenograft experiments showed rather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR

A Lagrangian Description of the Higher-Order Painlev\'e Equations

We derive the Lagrangians of the higher-order Painlev\'e equations using Jacobi's last multiplier technique. Some of these higher-order differential equations display certain remarkable properties like passing the Painlev\'e test and satisfy the conditions stated by Jur\'a$\check{s}$, (Acta Appl. Math. 66 (2001) 25--39), thus allowing for a Lagrangian description.Comment: 16 pages, to be published in Applied Mathematics and Computatio