A Neural-Astrocytic Network Architecture: Astrocytic calcium waves modulate synchronous neuronal activity

Understanding the role of astrocytes in brain computation is a nascent challenge, promising immense rewards, in terms of new neurobiological knowledge that can be translated into artificial intelligence. In our ongoing effort to identify principles endow-ing the astrocyte with unique functions in brain computation, and translate them into neural-astrocytic networks (NANs), we propose a biophysically realistic model of an astrocyte that preserves the experimentally observed spatial allocation of its distinct subcellular compartments. We show how our model may encode, and modu-late, the extent of synchronous neural activity via calcium waves that propagate intracellularly across the astrocytic compartments. This relationship between neural activity and astrocytic calcium waves has long been speculated but it is still lacking a mechanistic explanation. Our model suggests an astrocytic "calcium cascade" mechanism for neuronal synchronization, which may empower NANs by imposing periodic neural modulation known to reduce coding errors. By expanding our notions of information processing in astrocytes, our work aims to solidify a computational role for non-neuronal cells and incorporate them into artificial networks.Comment: International Conference on Neuromorphic Systems (ICONS) 201

Notes on S-Matrix of Non-critical N=2 String

In this paper we discuss the scattering S-matrix of non-critical N=2 string at tree level. First we consider the \hat{c}<1 string defined by combining the N=2 time-like linear dilaton SCFT with the N=2 Liouville theory. We compute three particle scattering amplitudes explicitly and find that they are actually vanishing. We also find an evidence that this is true for higher amplitudes. Next we analyze another \hat{c}<1 string obtained from the N=2 time-like Liouville theory, which is closely related to the N=2 minimal string. In this case, we find a non-trivial expression for the three point functions. When we consider only chiral primaries, the amplitudes are very similar to those in the (1,n) non-critical bosonic string.Comment: 27 pages, harvmac, section 5 modified: a relation to (1,n) non-critical bosonic string adde

Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys

Cortical injury, such as stroke, causes neurotoxic cascades that lead to rapid death and/or damage to neurons and glia. Axonal and myelin damage in particular, are critical factors that lead to neuronal dysfunction and impair recovery of function after injury. These factors can be exacerbated in the aged brain where white matter damage is prevalent. Therapies that can ameliorate myelin damage and promote repair by targeting oligodendroglia, the cells that produce and maintain myelin, may facilitate recovery after injury, especially in the aged brain where these processes are already compromised. We previously reported that a novel therapeutic, Mesenchymal Stem Cell derived extracellular vesicles (MSC-EVs), administered intravenously at both 24 h and 14 days after cortical injury, reduced microgliosis (Go et al. 2019), reduced neuronal pathology (Medalla et al. 2020), and improved motor recovery (Moore et al. 2019) in aged female rhesus monkeys. Here, we evaluated the effect of MSC-EV treatment on changes in oligodendrocyte maturation and associated myelin markers in the sublesional white matter using immunohistochemistry, confocal microscopy, stereology, qRT-PCR, and ELISA. Compared to vehicle control monkeys, EV-treated monkeys showed a reduction in the density of damaged oligodendrocytes. Further, EV-treatment was associated with enhanced myelin maintenance, evidenced by upregulation of myelin-related genes and increases in actively myelinating oligodendrocytes in sublesional white matter. These changes in myelination correlate with the rate of motor recovery, suggesting that improved myelin maintenance facilitates this recovery. Overall, our results suggest that EVs act on oligodendrocytes to support myelination and improves functional recovery after injury in the aged brain. SIGNIFICANCE: We previously reported that EVs facilitate recovery of function after cortical injury in the aged monkey brain, while also reducing neuronal pathology (Medalla et al. 2020) and microgliosis (Go et al. 2019). However, the effect of injury and EVs on oligodendrocytes and myelination has not been characterized in the primate brain (Dewar et al. 1999; Sozmen et al. 2012; Zhang et al. 2013). In the present study, we assessed changes in myelination after cortical injury in aged monkeys. Our results show, for the first time, that MSC-EVs support recovery of function after cortical injury by enhancing myelin maintenance in the aged primate brain

c < 1 String from Two Dimensional Black Holes

We study a topological string description of the c < 1 non-critical string whose matter part is defined by the time-like linear dilaton CFT. We show that the topologically twisted N=2 SL(2,R)/U(1) model (or supersymmetric 2D black hole) is equivalent to the c < 1 non-critical string compactified at a specific radius by comparing their physical spectra and correlation functions. We examine another equivalent description in the topological Landau-Ginzburg model and check that it reproduces the same scattering amplitudes. We also discuss its matrix model dual description.Comment: 36 pages, harvmac; acknowledgements, comments and references adde

Ramond-Ramond Fields, Fractional Branes and Orbifold Differential K-Theory

We study D-branes and Ramond-Ramond fields on global orbifolds of Type II string theory with vanishing H-flux using methods of equivariant K-theory and K-homology. We illustrate how Bredon equivariant cohomology naturally realizes stringy orbifold cohomology. We emphasize its role as the correct cohomological tool which captures known features of the low-energy effective field theory, and which provides new consistency conditions for fractional D-branes and Ramond-Ramond fields on orbifolds. We use an equivariant Chern character from equivariant K-theory to Bredon cohomology to define new Ramond-Ramond couplings of D-branes which generalize previous examples. We propose a definition for groups of differential characters associated to equivariant K-theory. We derive a Dirac quantization rule for Ramond-Ramond fluxes, and study flat Ramond-Ramond potentials on orbifolds.Comment: 46 pages; v2: typos correcte

Categorizing Different Approaches to the Cosmological Constant Problem

We have found that proposals addressing the old cosmological constant problem come in various categories. The aim of this paper is to identify as many different, credible mechanisms as possible and to provide them with a code for future reference. We find that they all can be classified into five different schemes of which we indicate the advantages and drawbacks. Besides, we add a new approach based on a symmetry principle mapping real to imaginary spacetime.Comment: updated version, accepted for publicatio

Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice.

Unlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor

Propionic acid promotes the virulent phenotype of Crohn's disease-associated adherent-invasive Escherichia coli

Propionic acid (PA) is a bacterium-derived intestinal antimicrobial and immune modulator used widely in food production and agriculture. Passage of Crohn’s disease-associated adherent-invasive Escherichia coli (AIEC) through a murine model, in which intestinal PA levels are increased to mimic the human intestine, leads to the recovery of AIEC with significantly increased virulence. Similar phenotypic changes are observed outside the murine model when AIEC is grown in culture with PA as the sole carbon source; such PA exposure also results in AIEC that persists at 20-fold higher levels in vivo. RNA sequencing identifies an upregulation of genes involved in biofilm formation, stress response, metabolism, membrane integrity, and alternative carbon source utilization. PA exposure also increases virulence in a number of E. coli isolates from Crohn’s disease patients. Removal of PA is sufficient to reverse these phenotypic changes. Our data indicate that exposure to PA results in AIEC resistance and increased virulence in its presence

Nachweis von PAK-metabolisierenden Mikroorganismen durch kulturelle und molekularbiologische Verfahren

Zielsetzung der Arbeit war der Nachweis von PAK-abbauenden Mikroorganismen in Umweltproben mittels klassischer mikrobiologischer Arbeitstechniken und molekular-biologischer Methoden. Durch selektive Anreicherung wurden Bakterien mit der Fähigkeit Polyzyklische Aromatische Kohlenwasserstoffe (PAK) abzubauen, in aquatischen und terrestrischen Umweltproben nachgewiesen. Unabhängig von der Belastung der Standorte mit PAK wurden aus allen untersuchten Habitaten Bakterien isoliert, die mit Naphthalin oder Phenanthren als alleiniger Kohlenstoff- und Energiequelle wachsen konnten. Die 23 isolierten PAK-abbauenden Bakterien konnten als Mitglieder der Gattungen Sphingomonas, Acidovorax, Comamonas, Pseudomonas, Rhodococcus und Paenibacillus identifiziert werden und waren somit den alpha-, beta- und gamma-Subklassen der Proteobakterien und den Entwicklungslinien der grampositiven Bakterien mit hohem und niedrigem GC-Gehalt der DNA zuzuordnen. Die größte Gruppe bildeten mit 10 der 23 Isolate Vertreter der Gattung Pseudomonas, die alle Naphthalin metabolisierten. Die Quantifizierung des Naphthalin-Abbaus mittels gaschromatographischer Verfahren zeigte, daß in Flüssigmedium vorhandenes kristallines Naphthalin (0,05%, w/v) von den meisten Stämmen nach nur zwei Tagen Kultivierungsdauer vollständig metabolisiert wurde. Die getesteten Rhodococcus Isolate bauten Naphthalin wesentlich langsamer ab, als die verschiedenen Isolate, die den Proteobakterien zugeordnet wurden. Der dreikernige Aromat Phenanthren wurde von den getesteten Bakterienstämmen langsamer abgebaut als Naphthalin. Innerhalb von fünf Tagen wurde die Phenanthrenmenge im Medium auf 40-60% der Ausgangsmenge reduziert. Die Untersuchung des Naphthalinabbaus durch Zellen, die zuvor in Naphthalin-haltigem Medium bzw. in Vollmedium vorkultiviert worden waren, ergab, daß die Enzyme für den Abbau von Naphthalin in Abwesenheit eines Induktors nicht exprimiert wurden. Ebenso zeigte sich, daß Zellen, die in Medium mit Naphthalin oder Phenanthren kultiviert wurden, wesentlich höhere Catechol 2,3-Dioxygenase (C23O)-Aktivitäten aufwiesen als in Voll-medium gewachsene Zellen. Zum Nachweis von PAK-Abbauern auf molekulargenetischer Ebene wurden, basierend auf bekannten Sequenzen, PCR-Primer und Oligonukleotidsonden für codierende Abschnitte der C23O entwickelt, und, in Kombination mit Primern und Oligonukleotidsonden, zur Detektion der initialen PAK-Dioxygenase (entwickelt von R. Moser, TU-Berlin), eingesetzt. Mit den entworfenen Primern und Sonden konnten die C23O-Sequenzabschnitte bei allen PAK-abbauenden Referenzstämmen und Isolaten, die der Gattung Pseudomonas und Sphingomonas zugehörten, spezifisch detektiert werden. Durch die Anwendung spezifischer Primer und Sonden konnten dabei die Gene der C23O für Vertreter der Pseudomonaden und Sphingomonaden getrennt voneinander erfaßt werden. Sequenzanalysen der erhaltenen PCR-Amplifikate zeigten, daß die C23O-Gene innerhalb der Gattungen Pseudomonas bzw. Sphingomonas mit über 75% Sequenzähnlichkeit sehr gut konserviert sind. Dagegen waren Sequenzen der katabolischen Gene der PAK-abbauenden Comamonas-, Acidovorax- oder Rhodococcus-Vertreter offensichtlich zu verschieden, verglichen mit den Pseudomonas- und Sphingomonas-Sequenzen, um sie mittels der entwickelten Primer und Sonden detektieren zu können. Die Diversität der C23O zeigte sich auch bei der spezifischen enzymatischen Aktivität, die im Bereich von 0,1 bis 650 mU mg-1 Protein variierte. Dabei wurde die höchste spezifische Aktivität für verschiedene Pseudomonas-Stämme nachgewiesen. Die entwickelten Primer wurden auf ihre Anwendbarkeit getestet, PAK-abbauende Bakterien in Umweltproben kultivierungsunabhängig zu detektieren. Verschiedene DNA-Isolierungsmethoden und Techniken zur Aufreinigung der isolierten DNA wurden getestet und variiert. Bei der DNA-Isolierung aus Belebtschlammproben wurden Substanzen coextrahiert, die stark hemmenden Einfluß auf die PCR hatten. Die weitere Aufreinigung der DNA führte zu starken Verlusten der ursprünglichen DNA-Mengen und damit zu einer Reduzierung der zu detektierenden Zielsequenzen. Die extrahierte und gereinigte DNA aus unterschiedlichen Belebtschlammproben wurde in der PCR zur Detektion von initiale Dioxygenase- und C23O-codierenden Genabschnitten eingesetzt. Während codierende Bereiche der initialen Dioxygenase in der Belebtschlammprobe der Kläranlage Gießen mit den entwickelten Primern nachgewiesen werden konnten (R. Moser, TU-Berlin), wurden bei der Verwendung der C23O-spezifischen Primer keine PCR-Amplifikate erhalten. Offensichtlich lag die Zahl der C23O-Zielsequenzen in den untersuchten Umweltpoben unterhalb des Detektionslimits. In der extrahierten DNA aus anderen Belebtschlammproben konnten C23O-codierende Abschnitte detektiert werden. Die erhaltenen PCR-Amplifikate waren aber in allen Fällen sehr schwach. Die Ergebnisse zeigen, daß zur Detektion von katabolischen Genen, die in geringen Konzentrationen in Umweltproben vorliegen, spezielle Methoden zur Aufreinigung der DNA-Rohextrakte etabliert werden müssen

Size Doesn't Matter: Towards a More Inclusive Philosophy of Biology

notes: As the primary author, O’Malley drafted the paper, and gathered and analysed data (scientific papers and talks). Conceptual analysis was conducted by both authors.publication-status: Publishedtypes: ArticlePhilosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations