Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis

The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson's disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington's disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood-brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.22 page(s

Bcl11b—A Critical Neurodevelopmental Transcription Factor—Roles in Health and Disease

B cell leukemia 11b (Bcl11b) is a zinc finger protein transcription factor with a multiplicity of functions. It works as both a genetic suppressor and activator, acting directly, attaching to promoter regions, as well as indirectly, attaching to promoter-bound transcription factors. Bcl11b is a fundamental transcription factor in fetal development, with important roles for the differentiation and development of various neuronal subtypes in the central nervous system (CNS). It has been used as a specific marker of layer V subcerebral projection neurons as well as striatal interneurons. Bcl11b also has critical developmental functions in the immune, integumentary and cardiac systems, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. Bcl11b has been implicated in a number of disease states including Huntington’s disease, Alzheimer’s disease, HIV and T-Cell malignancy, amongst others. Bcl11b is a fascinating protein whose critical roles in the CNS and other parts of the body are yet to be fully explicated. This review summarizes the current literature on Bcl11b and its functions in development, health, and disease as well as future directions for research

Perivascular macrophages create an intravascular niche for CD8 + T cell localisation prior to the onset of fatal experimental cerebral malaria

Objectives: The immunologic events that build up to the fatal neurological stage of experimental cerebral malaria (ECM) are incompletely understood. Here, we dissect immune cell behaviour occurring in the central nervous system (CNS) when Plasmodium berghei ANKA (PbA)-infected mice show only minor clinical signs. Methods: A 2-photon intravital microscopy (2P-IVM) brain imaging model was used to study the spatiotemporal context of early immunological events in situ during ECM. Results: Early in the disease course, antigen-specific CD8+ T cells came in contact and arrested on the endothelium of post-capillary venules. CD8+ T cells typically adhered adjacent to, or were in the near vicinity of, perivascular macrophages (PVMs) that line post-capillary venules. Closer examination revealed that CD8+ T cells crawled along the inner vessel wall towards PVMs that lay on the abluminal side of large post-capillary venules. 'Activity hotspots' in large post-capillary venules were characterised by T-cell localisation, activated morphology and clustering of PVM, increased abutting of post-capillary venules by PVM and augmented monocyte accumulation. In the later stages of infection, when mice exhibited neurological signs, intravascular CD8+ T cells increased in number and changed their behaviour, actively crawling along the endothelium and displaying frequent, short-term interactions with the inner vessel wall at hotspots. Conclusion: Our study suggests an active interaction between PVM and CD8+ T cells occurs across the blood-brain barrier (BBB) in early ECM, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology

P2X7 is an archaic scavenger receptor recognizing apoptotic neuroblasts in early human neurogenesis

The expression and function of P2X7 receptors in adult CNS have been widely studied, however, the roles of these purinergic receptors in human neural development has largely focused on the effects of receptor activation. Previous studies of embryonic and adult rodent neural precursors suggest adenosine triphosphate (ATP), the physiological agonist for P2X receptors, can act as a potent modifier of proliferation, migration and differentiation, mediated via intracellular calcium ([Ca2+]i) signaling. The P2X7 receptor has a ubiquitous distribution in the body but is most abundant on macrophages and microglia where its activation by ATP leads to secretion of proinflammatory cytokines. However, extracellular ATP concentrations in the CNS are usually at sub-micromolar levels suggesting that ATP-induced activation of the P2X7 receptor will not occur under physiological circumstances in the CNS. Another possible role for P2X7 receptors has been suggested by recent work on macrophages and neural precursor cells. In these studies the P2X7 receptor was shown to act as a scavenger receptor i.e. a receptor present on a phagocytotic cell which detects molecules present on the surface of apoptotic cells and facilitates phagocytosis of the apoptotic cell. In a recent study of human neural precursor cells (hNPCs) and neuroblasts isolated from human fetal telencephalons at 16-19 WG, our group showed that both P2X7Rhigh/DCXlow hNPCs and P2X7Rhigh/DCXhigh neuroblasts were capable of phagocytic engulfment of a range of targets including latex beads, apoptotic ReN cells and apoptotic neuroblasts. We found that these neuroblasts and their precursor cells expressed functional P2X7 receptors on their cell surface. Although expression of P2X7 is widespread in the cells of the neuroblast, it is those DCX+ neuroblasts with the highest expression of P2X7 which are actively phagocytic towards an autologous apoptotic neighbour or other phagocytic targets, including latex beads and apoptotic ReNcells. Pre-incubation of P2X7high neuroblasts with ATP or oxidized ATP inhibited phagocytosis of targets by these cells. Moreover siRNA knockdown of P2X7R also inhibited phagocytosis of the apoptotic targets. This review considers this major new role for the P2X7 receptor in early human neurogenesis

Momentum flow in black-hole binaries: II. Numerical simulations of equal-mass, head-on mergers with antiparallel spins

Research on extracting science from binary-black-hole (BBH) simulations has often adopted a "scattering matrix" perspective: given the binary's initial parameters, what are the final hole's parameters and the emitted gravitational waveform? In contrast, we are using BBH simulations to explore the nonlinear dynamics of curved spacetime. Focusing on the head-on plunge, merger, and ringdown of a BBH with transverse, antiparallel spins, we explore numerically the momentum flow between the holes and the surrounding spacetime. We use the Landau-Lifshitz field-theory-in-flat-spacetime formulation of general relativity to define and compute the density of field energy and field momentum outside horizons and the energy and momentum contained within horizons, and we define the effective velocity of each apparent and event horizon as the ratio of its enclosed momentum to its enclosed mass-energy. We find surprisingly good agreement between the horizons' effective and coordinate velocities. To investigate the gauge dependence of our results, we compare pseudospectral and moving-puncture evolutions of physically similar initial data; although spectral and puncture simulations use different gauge conditions, we find remarkably good agreement for our results in these two cases. We also compare our simulations with the post-Newtonian trajectories and near-field energy-momentum. [Abstract abbreviated; full abstract also mentions additional results.]Comment: Submitted to Phys. Rev.

Charged Black Holes in Two-Dimensional String Theory

We discuss two dimensional string theories containing gauge fields introduced either via coupling to open strings, in which case we get a Born-Infeld type action, or via heterotic compactification. The solutions to the modified background field equations are charged black holes which exhibit interesting space-time geometries. We also compute their masses and charges.Comment: 39 page

SO(2N) and SU(N) gauge theories in 2+1 dimensions

We perform an exploratory investigation of how rapidly the physics of SO(2N) gauge theories approaches its N=oo limit. This question has recently become topical because SO(2N) gauge theories are orbifold equivalent to SU(N) gauge theories, but do not have a finite chemical potential sign problem. We consider only the pure gauge theory and, because of the inconvenient location of the lattice strong-to-weak coupling 'bulk' transition in 3+1 dimensions, we largely confine our numerical calculations to 2+1 dimensions. We discuss analytic expectations in both D=2+1 and D=3+1, show that the SO(6) and SU(4) spectra do indeed appear to be the same, and show that a number of mass ratios do indeed appear to agree in the large-N limit. In particular SO(6) and SU(3) gauge theories are quite similar except for the values of the string tension and coupling, both of which differences can be readily understood.Comment: 27 pages, 9 figure

Error-analysis and comparison to analytical models of numerical waveforms produced by the NRAR Collaboration

The Numerical-Relativity-Analytical-Relativity (NRAR) collaboration is a joint effort between members of the numerical relativity, analytical relativity and gravitational-wave data analysis communities. The goal of the NRAR collaboration is to produce numerical-relativity simulations of compact binaries and use them to develop accurate analytical templates for the LIGO/Virgo Collaboration to use in detecting gravitational-wave signals and extracting astrophysical information from them. We describe the results of the first stage of the NRAR project, which focused on producing an initial set of numerical waveforms from binary black holes with moderate mass ratios and spins, as well as one non-spinning binary configuration which has a mass ratio of 10. All of the numerical waveforms are analysed in a uniform and consistent manner, with numerical errors evaluated using an analysis code created by members of the NRAR collaboration. We compare previously-calibrated, non-precessing analytical waveforms, notably the effective-one-body (EOB) and phenomenological template families, to the newly-produced numerical waveforms. We find that when the binary's total mass is ~100-200 solar masses, current EOB and phenomenological models of spinning, non-precessing binary waveforms have overlaps above 99% (for advanced LIGO) with all of the non-precessing-binary numerical waveforms with mass ratios <= 4, when maximizing over binary parameters. This implies that the loss of event rate due to modelling error is below 3%. Moreover, the non-spinning EOB waveforms previously calibrated to five non-spinning waveforms with mass ratio smaller than 6 have overlaps above 99.7% with the numerical waveform with a mass ratio of 10, without even maximizing on the binary parameters.Comment: 51 pages, 10 figures; published versio

A P2RX7 single nucleotide polymorphism haplotype promotes exon 7 and 8 skipping and disrupts receptor function

P2X7 is an ATP-gated membrane ion channel that is expressed by multiple cell types. Brief exposure to ATP induces the opening of a nonselective cation channel; while repeated or prolonged exposure induces formation of a transmembrane pore. This process may be partially regulated by alternative splicing of full-length P2RX7A pre-mRNA, producing isoforms that delete or retain functional domains. Here, we report cloning and expression of a novel P2RX7 splice variant, P2RX7L, that is, characterized by skipping of exons 7 and 8. In HEK 293 cells, expression of P2RX7L produces a protein isoform, P2X7L, that forms a heteromer with P2X7A. A haplotype defined by six single nucleotide polymorphisms (SNPs) (rs208307, rs208306, rs36144485, rs208308, rs208309, and rs373655596) promotes allele-specific alternative splicing, increasing mRNA levels of P2RX7L and another isoform, P2RX7E, which in addition has a truncated C-terminus. Skipping of exons 7 and 8 is predicted to delete critical amino acids in the ATP-binding site. P2X7L-transfected HEK 293 cells have phagocytic but not channel, pore, or membrane-blebbing function, and double-transfected P2X7L and P2X7A cells have reduced pore function. Heteromeric receptor complexes of P2X7A and P2X7L are predicted to have reduced numbers of ATP-binding sites, which potentially alters receptor function compared to homomeric P2X7A complexes