An O(N) symmetric extension of the Sine-Gordon Equation

We discuss an O(N) exension of the Sine-Gordon (S-G)equation which allows us to perform an expansion around the leading order in large-N result using Path-Integral methods. In leading order we show our methods agree with the results of a variational calculation at large-N. We discuss the striking differences for a non-polynomial interaction between the form for the effective potential in the Gaussian approximation that one obtains at large-N when compared to the N=1 case. This is in contrast to the case when the classical potential is a polynomial in the field and no such drastic differences occur. We find for our large-N extension of the Sine-Gordon model that the unbroken ground state is unstable as one increases the coupling constant (as it is for the original S-G equation) and we determine the stability criteria.Comment: 21 pages, Latex (Revtex4) v3:minor grammatical changes and addition

Resumming the large-N approximation for time evolving quantum systems

In this paper we discuss two methods of resumming the leading and next to leading order in 1/N diagrams for the quartic O(N) model. These two approaches have the property that they preserve both boundedness and positivity for expectation values of operators in our numerical simulations. These approximations can be understood either in terms of a truncation to the infinitely coupled Schwinger-Dyson hierarchy of equations, or by choosing a particular two-particle irreducible vacuum energy graph in the effective action of the Cornwall-Jackiw-Tomboulis formalism. We confine our discussion to the case of quantum mechanics where the Lagrangian is $L(x,\dot{x}) = (1/2) \sum_{i=1}^{N} \dot{x}_i^2 - (g/8N) [ \sum_{i=1}^{N} x_i^2 - r_0^2 ]^{2}$. The key to these approximations is to treat both the $x$ propagator and the $x^2$ propagator on similar footing which leads to a theory whose graphs have the same topology as QED with the $x^2$ propagator playing the role of the photon. The bare vertex approximation is obtained by replacing the exact vertex function by the bare one in the exact Schwinger-Dyson equations for the one and two point functions. The second approximation, which we call the dynamic Debye screening approximation, makes the further approximation of replacing the exact $x^2$ propagator by its value at leading order in the 1/N expansion. These two approximations are compared with exact numerical simulations for the quantum roll problem. The bare vertex approximation captures the physics at large and modest $N$ better than the dynamic Debye screening approximation.Comment: 30 pages, 12 figures. The color version of a few figures are separately liste

The Rise and Fall, and the Rise (Again) of Feminist Research in Music: 'What Goes Around Comes Around'

This article reports from a two-phase study that involved an analysis of the extant literature followed by a three-part survey answered by seventy-one women composers. Through these theoretical and empirical data, the authors explore the relationship between gender and music’s symbolic and cultural capital. Bourdieu’s theory of the habitus is employed to understand the gendered experiences of the female composers who participated in the survey. The article suggests that these female composers have different investments in gender but that, overall, they reinforce the male habitus given that the female habitus occupies a subordinate position in relation to that of the male. The findings of the study also suggest a connection between contemporary feminism and the attitudes towards gender held by the participants. The article concludes that female composers classify themselves, and others, according to gendered norms and that these perpetuate the social order in music in which the male norm dominates

Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells

WOS: 000402964700027PubMed ID: 28591655Astrocyte dysfunction and neuroinflammation are detrimental features in multiple pathologies of the CNS. Therefore, the development of methods that produce functional human astrocytes represents an advance in the study of neurological diseases. Here we report an efficient method for inflammation-responsive astrocyte generation from induced pluripotent stem cells (iPSCs) and embryonic stem cells. This protocol uses an intermediate glial progenitor stage and generates functional astrocytes that show levels of glutamate uptake and calcium activation comparable with those observed in human primary astrocytes. Stimulation of stem cell-derived astrocytes with interleukin-1 beta or tumor necrosis factor a elicits a strong and rapid pro-inflammatory response. RNA-sequencing transcriptome profiling confirmed that similar gene expression changes occurred in iPSC-derived and primary astrocytes upon stimulation with interleukin-1 beta. This protocol represents an important tool for modeling in-a-dish neurological diseases with an inflammatory component, allowing for the investigation of the role of diseased astrocytes in neuronal degeneration.Paul G. Allen Family Foundation; JPB Foundation; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; Annette C. Merle-Smith [R01 MH095741, U19MH106434]; G. Harold & Leila Y. Mathers Foundation; Flow Cytometry Core Facility of the Salk Institute; NIH-NCI CCSG [P30 014195]; Next Generation Sequencing Core Facility of the Salk Institute; Chapman Foundation; Helmsley Charitable Trust; Razavi Newman Integrative Genomics and Bioinformatics Core Facility of the Salk Institute; Swiss-NSF outgoing PD fellowship; Lynn and Edward Streim fellowship; EMBO long-term fellowship; Bettencourt Schueller Foundation; Philippe Foundation; Bob and Mary Jane EngmanFor the production of the iPSCs, the authors would like to acknowledge financial support from Janssen Pharmaceuticals. This work was supported by the Paul G. Allen Family Foundation, Bob and Mary Jane Engman, The JPB Foundation, The Leona M. and Harry B. Helmsley Charitable Trust grant # 2012-PG-MED002, Annette C. Merle-Smith, R01 MH095741 (F.H.G.), U19MH106434 (F.H.G.), and The G. Harold & Leila Y. Mathers Foundation. This work was supported by the Flow Cytometry Core Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195; the Next Generation Sequencing Core Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195; the Chapman Foundation and the Helmsley Charitable Trust and by The Razavi Newman Integrative Genomics and Bioinformatics Core Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195. This research was also supported by the Swiss-NSF outgoing PD fellowship (K.C.V.), Lynn and Edward Streim fellowship (K.C.V.), EMBO long-term fellowship (B.N.J.), the Bettencourt Schueller Foundation (B.N.J.), and the Philippe Foundation (B. N. J.). The authors would like to thank M. L. Gage for editorial comments

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with alpha-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic alpha-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic alpha-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of alpha-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel alpha-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic alpha-synuclein. Additionally, benztropine restored the alpha-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the alpha-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA

Species-specific maturation profiles of human, chimpanzee and bonobo neural cells.

Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species

Structure of a Double Transmembrane Fragment of a G-Protein-Coupled Receptor in Micelles

The structure and dynamic properties of an 80-residue fragment of Ste2p, the G-protein-coupled receptor for α-factor of Saccharomyces cerevisiae, was studied in LPPG micelles with the use of solution NMR spectroscopy. The fragment Ste2p(G31-T110) (TM1-TM2) consisted of 19 residues from the N-terminal domain, the first TM helix (TM1), the first cytoplasmic loop, the second TM helix (TM2), and seven residues from the first extracellular loop. Multidimensional NMR experiments on [15N], [15N, 13C], [15N, 13C, 2H]-labeled TM1-TM2 and on protein fragments selectively labeled at specific amino acid residues or protonated at selected methyl groups resulted in >95% assignment of backbone and side-chain nuclei. The NMR investigation revealed the secondary structure of specific residues of TM1-TM2. TALOS constraints and NOE connectivities were used to calculate a structure for TM1-TM2 that was highlighted by the presence of three α-helices encompassing residues 39–47, 49–72, and 80–103, with higher flexibility around the internal Arg58 site of TM1. RMSD values of individually superimposed helical segments 39–47, 49–72, and 80–103 were 0.25 ± 0.10 Å, 0.40 ± 0.13 Å, and 0.57 ± 0.19 Å, respectively. Several long-range interhelical connectivities supported the folding of TM1-TM2 into a tertiary structure typified by a crossed helix that splays apart toward the extracellular regions and contains considerable flexibility in the G56VRSG60 region. 15N-relaxation and hydrogen-deuterium exchange data support a stable fold for the TM parts of TM1-TM2, whereas the solvent-exposed segments are more flexible. The NMR structure is consistent with the results of biochemical experiments that identified the ligand-binding site within this region of the receptor