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It is known that many (upper) cluster algebras are not unique factorization domains. We exhibit the local factorization properties with respect to any given seed t: any non-zero element in a full rank upper cluster algebra can be uniquely written as the product of a cluster monomial in t and another element not divisible by the cluster variables in t. Our approach is based on introducing the valuation pairing on an upper cluster algebra: it counts the maximal multiplicity of a cluster variable among the factorizations of any given element. We apply the valuation pairing to obtain many results concerning factoriality, d-vectors, F-polynomials and the combinatorics of cluster Poisson variables. In particular, we obtain that full rank and primitive upper cluster algebras are factorial; an explanation of d-vectors using valuation pairing; a cluster monomial in non-initial cluster variables is determined by its F-polynomial; the F-polynomials of non-initial cluster variables are irreducible; and the cluster Poisson variables parametrize the exchange pairs of the corresponding upper cluster algebra. [ABSTRACT FROM AUTHOR]

These are slightly expanded notes of lectures given in April 2019 at the Isfahan school and conference on representations of algebras. We recall the formalism of derived categories and functors and survey invariance results for the Hochschild (co)homology of differential graded algebras and categories. [ABSTRACT FROM AUTHOR]

Given a tilting object of the derived category of an abelian category of finite global dimension, we give (under suitable finiteness conditions) a bound for the global dimension of its endomorphism ring. [ABSTRACT FROM AUTHOR]

We correct a mistake that occurred in the proof of the main theorem of "Singular Hochschild cohomology via singularity categories" and some inaccuracies in the proof of the reconstruction theorem. [ABSTRACT FROM AUTHOR]

Abstract We prove that derived equivalent algebras have isomorphic differential calculi in the sense of Tamarkin–Tsygan. [ABSTRACT FROM AUTHOR]

Abstract We show that the singular Hochschild cohomology (= Tate–Hochschild cohomology) of an algebra A is isomorphic, as a graded algebra, to the Hochschild cohomology of the differential graded enhancement of the singularity category of A. The existence of such an isomorphism is suggested by recent work by Zhengfang Wang. [ABSTRACT FROM AUTHOR]

Abstract Claire Amiot has classified the connected triangulated k -categories with finitely many isoclasses of indecomposables satisfying suitable hypotheses. We remark that her proof shows that these triangulated categories are determined by their underlying k -linear categories. We observe that, if the connectedness assumption is dropped, the triangulated categories are still determined by their underlying k -categories together with the action of the suspension functor on the set of isoclasses of indecomposables. [ABSTRACT FROM AUTHOR]

Inspired by recent work of Hernandez-Leclerc and Leclerc-Plamondon we investigate the link between Nakajima's graded affine quiver varieties associated with an acyclic connected quiver Q and the derived category of Q. As Leclerc-Plamondon have shown, the points of these varieties can be interpreted as representations of a category, which we call the (singular) Nakajima category S. We determine the quiver of S and the number of minimal relations between any two given vertices. We construct a δ-functor Φ taking each finitedimensional representation of S to an object of the derived category of Q. We show that the functor Φ establishes a bijection between the strata of the graded affine quiver varieties and the isomorphism classes of objects in the image of Φ. If the underlying graph of Q is an ADE Dynkin diagram, the image is the whole derived category; otherwise, it is the category of 'line bundles over the non-commutative curve given by Q'. We show that the degeneration order between strata corresponds to Jensen-Su-Zimmermann's degeneration order on objects of the derived category. Moreover, if Q is an ADE Dynkin quiver, the singular category S is weakly Gorenstein of dimension 1 and its derived category of singularities is equivalent to the derived category of Q. [ABSTRACT FROM AUTHOR]

The amoeba-resistant bacterium Legionella pneumophila causes Legionnaires' disease and employs a type IV secretion system (T4SS) to replicate in the unique, ER-associated Legionella-containing vacuole (LCV). The large fusion GTPase Sey1/atlastin is implicated in ER dynamics, ER-derived lipid droplet (LD) formation, and LCV maturation. Here, we employ cryo-electron tomography, confocal microscopy, proteomics, and isotopologue profiling to analyze LCV-LD interactions in the genetically tractable amoeba Dictyostelium discoideum. Dually fluorescence-labeled D. discoideum producing LCV and LD markers revealed that Sey1 as well as the L. pneumophila T4SS and the Ran GTPase activator LegG1 promote LCV-LD interactions. In vitro reconstitution using purified LCVs and LDs from parental or ?sey1 mutant D. discoideum indicated that Sey1 and GTP promote this process. Sey1 and the L. pneumophila fatty acid transporter FadL were implicated in palmitate catabolism and palmitate-dependent intracellular growth. Taken together, our results reveal that Sey1 and LegG1 mediate LD- and FadL-dependent fatty acid metabolism of intracellular L. pneumophila. [ABSTRACT FROM AUTHOR]

We prove the derived invariance of the cap product for associative algebras projective over a commutative ring. [ABSTRACT FROM AUTHOR]

The |$\textbf{g}$| -vector fan of a finite-dimensional algebra is a fan whose rays are the |$\textbf{g}$| -vectors of its two-term presilting objects. We prove that the |$\textbf{g}$| -vector fan of a tame algebra is dense. We then apply this result to obtain a near classification of quivers for which the closure of the cluster |$\textbf{g}$| -vector fan is dense or is a half-space, using the additive categorification of cluster algebras by means of Jacobian algebras. As another application, we prove that for quivers with potentials arising from once-punctured closed surfaces, the stability and cluster scattering diagrams only differ by wall-crossing functions on the walls contained in a separating hyperplane. The appendix is devoted to the construction of truncated twist functors and their adjoints. [ABSTRACT FROM AUTHOR]

Abstract: Inspired by recent work of Cerulli, Feigin and Reineke on desingularizations of quiver Grassmannians of representations of Dynkin quivers, we obtain desingularizations in considerably more general situations and in particular for Grassmannians of modules over iterated tilted algebras of Dynkin type. Our desingularization map is constructed from Nakajima's desingularization map for graded quiver varieties. [Copyright &y& Elsevier]

Fomin–Zelevinsky conjectured that in any cluster algebra, the cluster monomials are linearly independent and that the exchange graph and cluster complex are independent of the choice of coefficients. We confirm these conjectures for all skew-symmetric cluster algebras. [ABSTRACT FROM AUTHOR]

Using techniques due to Dwyer–Greenlees–Iyengar, we construct weight structures in triangulated categories generated by compact objects. We apply our result to show that, for a dg category whose homology vanishes in negative degrees and is semi-simple in degree 0, each simple module over the homology lifts to a dg module which is unique up to isomorphism in the derived category. This allows us, in certain situations, to deduce the existence of a canonical t-structure on the perfect derived category of a dg algebra. From this, we can obtain a bijection between hearts of t-structures and sets of the so-called simple-minded objects for some dg algebras (including Ginzburg algebras associated to quivers with potentials). In three appendices, we elucidate the relation between Milnor colimits and homotopy colimits and clarify the construction of t-structures from sets of compact objects in triangulated categories as well as the construction of a canonical weight structure on the unbounded derived category of a nonpositive dg category. [ABSTRACT FROM AUTHOR]

We define n-angulated categories by modifying the axioms of triangulated categories in a natural way. We show that Heller's parametrization of pre-triangulations extends to pre- n-angulations. We obtain a large class of examples of n-angulated categories by considering ( n − 2)-cluster tilting subcategories of triangulated categories which are stable under the ( n − 2)-nd power of the suspension functor. As an application, we show how n-angulated Calabi-Yau categories yield triangulated Calabi-Yau categories of higher Calabi-Yau dimension. Finally, we sketch a link to algebraic geometry and string theory. [ABSTRACT FROM AUTHOR]

For skew-symmetric acyclic quantum cluster algebras, we express the quantum F-polynomials and the quantum cluster monomials in terms of Serre polynomials of quiver Grassmannians of rigid modules. As byproducts, we obtain the existence of counting polynomials for these varieties and the positivity conjecture with respect to acyclic seeds. These results complete previous work by Caldero and Reineke and confirm a recent conjecture by Rupel. [ABSTRACT FROM AUTHOR]

Integral cluster categories of acyclic quivers have recently been used in the representation-theoretic approach to quantum cluster algebras. We show that over a principal ideal domain, such categories behave much better than one would expect: They can be described as orbit categories, their indecomposable rigid objects do not depend on the ground ring and the mutation operation is transitive. [ABSTRACT FROM PUBLISHER]

Abstract: We prove that the frieze sequences of cluster variables associated with the vertices of an affine quiver satisfy linear recurrence relations. In particular, we obtain a proof of a recent conjecture by Assem–Reutenauer–Smith. [Copyright &y& Elsevier]

We define and investigate deformed n-Calabi--Yau completions of homologically smooth differential graded (== dg) categories. Important examples are: deformed preprojective algebras of connected non-Dynkin quivers, Ginzburg dg algebras associated to quivers with potentials and dg categories associated to the category of coherent sheaves on the canonical bundle of a smooth variety. We show that deformed Calabi--Yau completions do have the Calabi--Yau property and that their construction is compatible with derived equivalences and with localizations. In particular, Ginzburg dg algebras have the Calabi--Yau property. We show that deformed 3-Calabi--Yau completions of algebras of global dimension at most 2 are quasi-isomorphic to Ginzburg dg algebras and apply this to the study of cluster-tilted algebras and to the construction of derived equivalences associated to mutations of quivers with potentials. In the appendix, Michel Van den Bergh uses non-commutative differential geometry to give an alternative proof of the fact that Ginzburg dg algebras have the Calabi--Yau property. [ABSTRACT FROM AUTHOR]

In a recent paper, Iyama and Yoshino considered two interesting examples of isolated singularities over which it is possible to classify the indecomposable maximal Cohen–Macaulay modules in terms of linear algebra data. In this paper, we present two new approaches to these examples. In the first approach we give a relation with cluster categories. In the second approach we use Orlov’s result on the graded singularity category. [ABSTRACT FROM AUTHOR]

Abstract: We show that Derksen–Weyman–Zelevinsky''s mutations of quivers with potential yield equivalences of suitable 3-Calabi–Yau triangulated categories. Our approach is related to that of Iyama–Reiten and ‘Koszul dual’ to that of Kontsevich–Soibelman. It improves on previous work by Vitória. In Appendix A, the first-named author studies pseudo-compact derived categories of certain pseudo-compact dg algebras. [Copyright &y& Elsevier]

Abstract: Since curved dg algebras, and modules over them, have differentials whose square is not zero, these objects have no cohomology, and there is no classical derived category. For different purposes, different notions of “derived” categories have been introduced in the literature. In this article, we show that for some concrete curved dg algebras, these derived categories vanish. This happens for example for the initial curved dg algebra whose module category is the category of precomplexes, and for certain deformations of dg algebras. [Copyright &y& Elsevier]

We determine the Hall algebra, in the sense of B. Toën, of the algebraic triangulated category generated by a spherical object. [ABSTRACT FROM PUBLISHER]

In this paper we show that, in general, first-order Morita deformations are too limited to capture the second Hochschild cohomology of a differential graded category. For differential graded categories with bounded above cohomology, the Morita deformations do constitute a part of the Hochschild cohomology. [ABSTRACT FROM PUBLISHER]

The cluster category is a triangulated category introduced for its combinatorial similarities with cluster algebras. We prove that a cluster algebra $\mathcal{A}$ of finite type can be realized as a Hall algebra, called exceptional Hall algebra, of the cluster category. This realization provides a natural basis for $\mathcal{A}$ . We prove new results and formulate conjectures on ‘good basis’ properties, positivity, denominator theorems and toric degenerations. [ABSTRACT FROM AUTHOR]

Abstract: By a theorem due to the first author, the bounded derived category of a finite dimensional algebra over a field embeds fully faithfully into the stable category over its repetitive algebra. This embedding is an equivalence if the algebra is of finite global dimension. The purpose of this paper is to investigate the relationship between the derived category and the stable category over the repetitive algebra from various points of view for algebras of infinite global dimension. The most satisfactory results are obtained for Gorenstein algebras, especially for selfinjective algebras. [Copyright &y& Elsevier]

Abstract: We prove that in a 2-Calabi–Yau triangulated category, each cluster tilting subcategory is Gorenstein with all its finitely generated projectives of injective dimension at most one. We show that the stable category of its Cohen–Macaulay modules is 3-Calabi–Yau. We deduce in particular that cluster-tilted algebras are Gorenstein of dimension at most one, and hereditary if they are of finite global dimension. Our results also apply to the stable (!) endomorphism rings of maximal rigid modules of [Christof Geiß, Bernard Leclerc, Jan Schröer, Rigid modules over preprojective algebras, arXiv: math.RT/0503324, Invent. Math., in press]. In addition, we prove a general result about relative 3-Calabi–Yau duality over non-stable endomorphism rings. This strengthens and generalizes the Ext-group symmetries obtained in [Christof Geiß, Bernard Leclerc, Jan Schröer, Rigid modules over preprojective algebras, arXiv: math.RT/0503324, Invent. Math., in press] for simple modules. Finally, we generalize the results on relative Calabi–Yau duality from 2-Calabi–Yau to d-Calabi–Yau categories. We show how to produce many examples of d-cluster tilted algebras. [Copyright &y& Elsevier]

We prove existence of equalizers in certain categories of cocomplete cocategories. This allows us to complete the proof of the fact that A1-functor categories arise as internal Hom-objects in the category of differential graded cocomplete augmented cocategories. [ABSTRACT FROM AUTHOR]

Abstract: In the acyclic case, we establish a one-to-one correspondence between the tilting objects of the cluster category and the clusters of the associated cluster algebra. This correspondence enables us to solve conjectures on cluster algebras. We prove a multiplicativity theorem, a denominator theorem, and some conjectures on properties of the mutation graph. As in the previous article, the proofs rely on the Calabi–Yau property of the cluster category. [Copyright &y& Elsevier]

Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca2+-dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca2+-buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca2+ buffers are valuable because they facilitate rapid relaxation times of Ca2+ transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca2+ buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca2+ disregulation and excitotoxic cell damage. [Copyright &y& Elsevier]

Abstract: A variety of studies demonstrated a crucial role of mitochondria for clearance of Ca2+ loads in motoneurons. However, previous reports rarely addressed the potential influence of cell dialysis during patch-clamp recordings or temperature on mitochondrial processes. We therefore developed a protocol allowing investigation of Ca2+ dynamics in “undisturbed” AM-ester loaded hypoglossal motoneurons in a slice preparation. By comparing our findings to previous results, we argue against a significant disturbance of mitochondrial buffering by cell dialysis. By varying bath temperatures between 19 and 32°C, we show that temperature alters the rate of mitochondrial uptake but not the relative contribution to maintenance of Ca2+ homeostasis. The results further indicate that mitochondria in hypoglossal motoneurons participate in intracellular Ca2+ regulation at concentrations much lower than has been generally observed for other neurons or neuroendocrine cells. Taken together, our findings further support the important role of mitochondria as regulators of Ca2+ homeostasis in motoneurons. [Copyright &y& Elsevier]

We interpret Hochschild cohomology as the Lie algebra of the derived Picard group and deduce that it is preserved under derived equivalences. [Copyright &y& Elsevier]

Motoneurones (MNs) are particularly affected by the inhibition of mitochondrial metabolism, which has been linked to their selective vulnerability during pathophysiological states like hypoxia and amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To elucidate underlying events, we used sodium cyanide (CN) as a pharmacological inhibitor of complex IV of the mitochondrial respiratory chain ('chemical hypoxia') and investigated the cellular response in vulnerable and resistant neurone types. Bath application of 2 mM CN activated TTX-insensitive Na+ conductances in vulnerable hypoglossal MNs, which depolarized these MNs by 10.2 ± 1.1 mV and increased their action potential activity. This response was mimicked by sodium azide (2 mM) and largely prevented by preincubation with the antioxidants ascorbic acid (1 mM) and Trolox (750 µM), indicating an involvement of reactive oxygen species (ROS) in the activation mechanism. CN also elevated cytosolic [Ca2+] levels through (i) Ca2+ release from mitochondria-controlled stores, (ii) significant retardation of cytosolic Ca2+ clearance rates, even when cytosolic ATP levels were held constant during whole-cell recording, and (iii) secondary Ca2+ influx during elevated firing rates. Blocking mitochondrial ATP production additionally raised cytosolic Ca2+ levels and prolonged recovery of Ca2+ transients with a delay of 5-6 min. Comparative studies on hypoglossal MNs, facial MNs and dorsal vagal neurones suggested that CN responses were dominated by the activation of K+ conductances in resistant neurones, thus reducing excitability during mitochondrial inhibition. In summary, our observations therefore support a model where selective MN vulnerability results from a synergistic accumulation of risk factors, including low cytosolic Ca2+ buffering, strong mitochondrial impact on... [ABSTRACT FROM AUTHOR]

The original paper did not clearly state that Pierre-Guy Plamondon and Toshiya Yurikusa were the author of the paper, but that Bernhard Keller was the author of the appendix. One digram originally appeared as Graph It should have appeared as Graph In reference 12 "Yildirim" should have appeared as "Yildirim". [Extracted from the article]

For any finite dimensional algebra Λ given by a quiver with relations, we prove that its dg singularity category is quasi-equivalent to the perfect dg derived category of a dg Leavitt path algebra. The result might be viewed as a deformed version of the known description of the dg singularity category of a radical-square-zero algebra in terms of a Leavitt path algebra with trivial differential. The above result is achieved in two steps. We first introduce the singular Yoneda dg category of Λ, which is quasi-equivalent to the dg singularity category of Λ. The construction of this new dg category follows from a general operation for dg categories, namely an explicit dg localization inverting a natural transformation from the identity functor to a dg endofunctor. This localization turns out to be quasi-equivalent to a dg quotient category. Secondly, we prove that the endomorphism algebra of the quotient of Λ modulo its Jacobson radical in the singular Yoneda dg category is isomorphic to the dg Leavitt path algebra. The appendix is devoted to an alternative proof of the result using Koszul-Moore duality and derived localizations. [ABSTRACT FROM AUTHOR]

Let k be an algebraically closed field and A a finite-dimensional k-algebra. In this note, we determine complexes which compute the Hochschild homology of the canonical dg enhancement of the bounded derived category of A and of the canonical dg enhancement of the singularity category of A. As an application, we obtain a new approach to the computation of Hochschild homology of Leavitt path algebras. [ABSTRACT FROM AUTHOR]

Given a triangulated 2-Calabi–Yau category C and a cluster-tilting subcategory T, the index of an object X of C is a certain element of the Grothendieck group of the additive category T. In this note, we show that a rigid object of C is determined by its index, that the indices of the indecomposables of a cluster-tilting subcategory T′ form a basis of the Grothendieck group of T and that, if T and T′ are related by a mutation, then the indices with respect to T and T′ are related by a certain piecewise linear transformation introduced by Fomin and Zelevinsky in their study of cluster algebras with coefficients. This allows us to give a combinatorial construction of the indices of all rigid objects reachable from the given cluster-tilting subcategory T. Conjecturally, these indices coincide with Fomin–Zelevinsky's g-vectors. [ABSTRACT FROM PUBLISHER]

Subtype-specific pharmacological compounds represent important tools to identify the molecular components of synaptically activated glutamate receptors in central neurones. Here, we utilized a collection of subtype-specific antagonists and modulators to investigate the functional profile of glutamate receptors in identified synapses in thin slices of the cerebellum, hippocampus and brain stem. During whole-cell patch-clamp recordings α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate (AMPA/KA) receptor-mediated synaptic currents (EPSCs) in cerebellar Purkinje cells were (i) prolonged by 100 μm cyclothiazide, (ii) not significantly changed after preincubation in 10 μm concanavalin A, (iii) not affected by 1 μm Evans Blue or polyamine toxin analogue N-(4-hydroxyphenylpropanolyl)-spermine (NHPPS), but (iv) significantly reduced by high (≥ 100 μm) concentrations of Evans Blue. These pharmacological properties were distinct from those observed in hippocampal granule cells and brain stem interneurones and markedly different from those of recombinant glutamate receptor channels GluR1–GluR6 previously investigated in heterologous expression systems. [ABSTRACT FROM AUTHOR]

Let t ∈ N, let K be a field and let VKt denote the class of all algebraic vector bundles over the projective space PKt The cohomology table of a bundle ε ∈ VKt is defined as the family of nonnegative integers hε := (hi(PKt, ε(n)))(i,n)∈N0×Z. A set S ⊆ {0, . . ., t}×Z is said to be a bounding pattern for the cohomology of vector bundles over PKt if for each family (h(i,n))(i,n)∈S of non-negative integers, the set of cohomology tables {hε | ε ∈ VKt : hεi (n) ≤ h(i,n) for all (i, n) ∈ S} is finite. Our main result says that this is the case if and only if S contains a quasi-diagonal of width t, that is, a set of the form {(i, ni)| i = 0, . . ., t} with integers n0 > n1 > · · · > nt. [ABSTRACT FROM AUTHOR]

The University has quite a big campus located not far from the city center, in a quiet and convenient area with many facilities. The School was supported by Centre International de Mathématiques Pures et Appliquées (CIMPA), Agence Universitaire de la Francophonie (AUF), Institute for Research in Fundamental Sciences-Isfahan branch (IPM-Isfahan), Iran National Science Fundation (INSF) and University of Isfahan. Representation theory is a central branch of modern mathematics that studies realizations of abstract non-linear structures using classical linear and combinatorial concrete structures like matrices, linear operators and quivers. [Extracted from the article]

Abstract: In this article we study Cohen–Macaulay modules over one-dimensional hypersurface singularities and the relationship with the representation theory of associative algebras using methods of cluster tilting theory. We give a criterion for existence of cluster tilting objects and their complete description by homological methods, using higher almost split sequences and results from birational geometry. We obtain a large class of 2-CY tilted algebras which are finite-dimensional symmetric and satisfy . In particular, we compute 2-CY tilted algebras for simple and minimally elliptic curve singularities. [Copyright &y& Elsevier]

(1) Serotonin (5HT)-mediated calcium signaling was investigated in hypoglossal motoneurons (HGMs) in brain stem slices of neonatal mice. Electrical activity and associated calcium signaling were studied by simultaneous patch clamp recordings and high resolution calcium imaging. (2) Bath application of 5HT (5–50 μM) depolarized membrane potential of HGMs and generated action potential discharges that were accompanied by elevations in intracellular calcium concentrations ([Ca2+]i) in the soma and dendrites. Current-evoked bursts of action potentials were more intense in the presence of 5HT; however, the corresponding calcium signals were reduced. (3) The 5HT2 receptor agonist α-Methyl-5HT (25, 50 μM) had effects on membrane potential, discharge properties and [Ca]i that were identical to those observed for 5HT, whereas the 5HT3 receptor agonist 1-(m-chlorophenyl) biguanide (50 μM) had no effect on membrane properties or intracellular calcium levels. (4) 8-OHDPAT (25, 50 μM), a 5HT1A receptor agonist, was without effect on steady-state membrane potential or basal [Ca]i. Similar to 5HT and α-Methyl-5HT, 8-OHDPAT depressed stimulus-evoked calcium transients in current and voltage clamp mode. (5) Our results suggest that calcium profiles in hypoglossal motoneurons are differentially regulated by 5HT1A and 5HT2 receptors. Activation of 5HT1A receptors primarily reduced voltage-activated Ca2+ signals without a significant impact on basal [Ca]i. In contrast, activation of 5HT2 receptors initiated a net inward current followed by membrane depolarization, where the resulting pattern of action potential discharges represents the essential determinant of global elevations in [Ca2+]i. Taken together, our results therefore identify 5HT-dependent signal pathways as a versatile tool to modulate hypoglossal motoneuron excitability under various physiological and pathophysiological conditions. [Copyright &y& Elsevier]

Key points So far, increased excitability and calcium handling problems have been discussed as causes for motoneuron death in amyotrophic lateral sclerosis (ALS) mainly on the basis of studies in juvenile presymptomatic mice., We developed a brainstem preparation to analyse excitability and calcium handling during disease progression up to disease endstage of motoneurons in an ALS mouse model., Increased excitability of motoneurons is not seen at disease endstage, challenging this factor as a direct cause for motoneuron death in ALS., We show that calcium handling is remodelled during disease progression from mitochondrial uptake to mitochondrial uptake failure and increased plasma membrane extrusion, providing a compensatory mechanism that fails at disease endstage and might lead to a toxic calcium overload of the cells., Supporting this newly described compensatory endeavour of the motoneurons might be a promising therapeutic strategy., Abstract Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that targets some somatic motoneuron populations, while others, e.g. those of the oculomotor system, are spared. The pathophysiological basis of this pattern of differential vulnerability, which is preserved in a transgenic mouse model of amyotrophic lateral sclerosis (SOD1G93A), and the mechanism of neurodegeneration in general are unknown. Hyperexcitability and calcium dysregulation have been proposed by others on the basis of data from juvenile mice that are, however, asymptomatic. No studies have been done with symptomatic mice following disease progression to the disease endstage. Here, we developed a new brainstem slice preparation for whole-cell patch-clamp recordings and single cell fura-2 calcium imaging to study motoneurons in adult wild-type and SOD1G93A mice up to disease endstage. We analysed disease-stage-dependent electrophysiological properties and intracellular Ca2+ handling of vulnerable hypoglossal motoneurons in comparison to resistant oculomotor neurons. Thereby, we identified a transient hyperexcitability in presymptomatic but not in endstage vulnerable motoneurons. Additionally, we revealed a remodelling of intracellular Ca2+ clearance within vulnerable but not resistant motoneurons at disease endstage characterised by a reduction of uniporter-dependent mitochondrial Ca2+ uptake and enhanced Ca2+ extrusion across the plasma membrane. Our study challenged the notion that hyperexcitability is a direct cause of neurodegeneration in SOD1G93A mice, but molecularly identified a Ca2+ clearance deficit in motoneurons and an adaptive Ca2+ handling strategy that might be targeted by future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons. To analyze the progressive motor deficits during the course of this disease, we investigated fatigability and ability of recovery of spinal motor neurons by testing monosynaptic reflex transmission with increasing stimulus frequencies in the lumbar spinal cord of the SOD1(G93A) mouse model for ALS in a comparison with wild-type (WT) mice. Monosynaptic reflexes in WT and SOD1(G93A) mice without behavioral deficits showed no difference with respect to their resistance to increasing stimulus frequencies. During the progression of motor deficits in SOD1(G93A) mice, the vulnerability of monosynaptic reflexes to higher frequencies increased, the required time for reflex recovery was extended, and recovery was often incomplete. Fatigability and demand for recovery of spinal motor neurons in SOD1(G93A) mice rose with increasing motor deficits. This supports the assumption that impairment of the energy supply may contribute to the pathogenesis of ALS. [ABSTRACT FROM AUTHOR]

The article focuses on amyotrophic lateral sclerosis (ALS), which is a neurodegenerative disease characterized by progressive loss of motor neurons. It focuses on the fatigability and ability of recovery of spinal motor neurons by testing monosynaptic reflex transmission with increasing stimulus frequencies in the lumbar spinal cord of the mouse model for ALS. It stattes that fatigability and demand for recovery of spinal motor neurons in mice rose with increasing motor deficits.

Abstract: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of brainstem and spinal motoneurons. The pathomechanism of degeneration is still incompletely understood, but includes a disruption in cellular Ca2+ homeostasis. Here we report a quantitative microfluorometric analysis of the Ca2+ homeostasis in vulnerable hypoglossal motoneurons of neonatal mutant (G93A) SOD1 transgenic mice, a mouse model of human ALS. Ca2+ transient decay times (τ =0.3s), extrusion rates (γ =92s−1) and exceptionally low intrinsic Ca2+ binding ratios (κ S =30) were found to be in the same range as compared to non-transgenic animals. Together with the previous observation of high Ca2+ binding ratios in ALS-resistant neurons (e.g. oculomotor), this supports the assumption that low Ca2+ buffering in vulnerable motoneurons represents a significant risk factor for degeneration. On the other hand, alterations in buffering properties by expression of mutant SOD1 are unlikely to be involved in disease initiation. [Copyright &y& Elsevier]

Background: Infections can aggravate the course of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in the anti-oxidant enzyme Cu,Zn superoxide dismutase (EC 1.15.1.1, SOD1) are associated with familial ALS. Streptococcus pneumoniae, the most frequent respiratory pathogen, causes damage by the action of the cholesterol-binding virulence factor pneumolysin and by stimulation of the innate immune system, particularly via Toll-like-receptor 2. Methods: SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) and SH-SY5Y neuroblastoma cells transfected with wildtype SOD1 were both exposed to pneumolysin and in co-cultures with cultured human macrophages treated with the Toll like receptor 2 agonist N-palmitoyl-S-[2,3-bis(palmitoyloxy)(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine x 3 HCl (Pam3CSK4). Cell viability and apoptotic cell death were compared morphologically and by in-situ tailing. With the help of the WST-1 test, cell viability was quantified, and by measurement of neuron-specific enolase in the culture supernatant neuronal damage in co-cultures was investigated. Intracellular calcium levels were measured by fluorescence analysis using fura-2 AM. Results: SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) were more vulnerable to the neurotoxic action of pneumolysin and to the attack of monocytes stimulated by Pam3CSK4 than SHSY5Y cells transfected with wild-type human SOD1. The enhanced pneumolysin toxicity in G93A-SOD1 neuronal cells depended on the inability of these cells to cope with an increased calcium influx caused by pores formed by pneumolysin. This inability was caused by an impaired capacity of the mitochondria to remove cytoplasmic calcium. Treatment of G93A-SOD1 SHSY5Y neuroblastoma cells with the antioxidant N-acetylcysteine reduced the toxicity of pneumolysin. Conclusion: The particular vulnerability of G93A-SOD1 neuronal cells to hemolysins and inflammation may be partly responsible for the clinical deterioration of ALS patients during infections. These findings link infection and motor neuron disease and suggest early treatment of respiratory infections in ALS patients. [ABSTRACT FROM AUTHOR]

The high affinity, Na+-dependent, electrogenic glial l-glutamate transporters GLAST1 and GLT1, and two neuronal EAAC1 and EAAT4, regulate the neurotransmitter concentration in excitatory synapses of the central nervous system. We dissected the function of the individual transporters in the monogenic null allelic mouse lines, glast1−/− and eaac1−/−, and the derived double mutant glast−/−eaac1−/−. Unexpectedly, the biochemical analysis and the behavioral phenotypes of these null allelic mouse lines were inconspicuous. Inhibition studies of the Na+-dependent glutamate transport by plasma membrane vesicles and by isolated astrocytes of wt and glast1−/− mouse brains indicated the pivotal compensatory role of GLT1 in the absence particularly of GLAST1 and GLAST1 and EAAC1 mutant mice. In electrophysiological studies, the decay rate of excitatory postsynaptic currents (EPSCs) of Purkinje cells (PC) after selective activation of parallel and climbing fibers proved to be similar in wt and eaac1−/−, but was significantly prolonged in glast1−/− PCs. Bath application of the glutamate uptake blocker SYM2081 prolonged EPSC decay profiles in both wt and double mutant glast1−/−eaac1−/− PCs by 286% and 229%, respectively, indicating a prominent role of compensatory glutamate transport in shaping glast1−/−eaac1−/− EPSCs. [Copyright &y& Elsevier]

Neuronal injury in bacterial meningitis is caused by the interplay of host inflammatory responses and direct bacterial toxicity. We investigated the mechanisms by which pneumolysin, a cytosolic pneumococcal protein, induces damage to neurons. The toxicity after exposure of human SH-SY5Y neuroblastoma cells and hippocampal organotypic cultures to pneumolysin was time- and dose-dependent. Pneumolysin led to a strong calcium influx apparently mediated by pores on the cell membrane formed by the toxin itself and not by voltage-gated calcium channels. Buffering of intracellular calcium with BAPTA-AM [1, 2-bis (o-aminophenoxy) ethane N, N, N′, N′-tetraacetic acid tetra(acetomethoxyl) ester] improved survival of neuronal cells following challenge with pneumolysin. Western blotting revealed increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) as early as 30 min after challenge with pneumolysin. SB 203580, a potent and selective inhibitor of p38 MAPK, rescued human neuronal cells from pneumolysin-induced death. Inhibition of the mitochondrial permeability transition pore using bongkrekate and caspase inhibition also improved survival following challenge with the toxin. Modulation of cell death pathways activated by pneumolysin may influence the outcome of pneumococcal meningitis. [Copyright &y& Elsevier]