Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/cn400167nCorticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits.British Neuro-pathological Society, North Staffordshire Medical Institute, and The University of Nottingham

A Review of the N-bound and the Maximal Mass Conjectures Using NUT-Charged dS Spacetimes

The proposed dS/CFT correspondence remains an intriguing paradigm in the context of string theory. Recently it has motivated two interesting conjectures: the entropic N-bound and the maximal mass conjecture. The former states that there is an upper bound to the entropy in asymptotically de Sitter spacetimes, given by the entropy of pure de Sitter space. The latter states that any asymptotically de Sitter spacetime cannot have a mass larger than the pure de Sitter case without inducing a cosmological singularity. Here we review the status of these conjectures and demonstrate their limitation. We first describe a generalization of gravitational thermodynamics to asymptotically de Sitter spacetimes, and show how to compute conserved quantities and gravitational entropy using this formalism. From this we proceed to a discussion of the N-bound and maximal mass conjectures. We then illustrate that these conjectures are not satisfied for certain asymptotically de Sitter spacetimes with NUT charge. We close with a presentation of explicit examples in various spacetime dimensionalities.Comment: 49 pages, 17 figures, a few typos corrected, addendum added with regard to some references that were later brought to our attentio

Angular momentum and an invariant quasilocal energy in general relativity

Owing to its transformation property under local boosts, the Brown-York quasilocal energy surface density is the analogue of E in the special relativity formula: E^2-p^2=m^2. In this paper I will motivate the general relativistic version of this formula, and thereby arrive at a geometrically natural definition of an `invariant quasilocal energy', or IQE. In analogy with the invariant mass m, the IQE is invariant under local boosts of the set of observers on a given two-surface S in spacetime. A reference energy subtraction procedure is required, but in contrast to the Brown-York procedure, S is isometrically embedded into a four-dimensional reference spacetime. This virtually eliminates the embeddability problem inherent in the use of a three-dimensional reference space, but introduces a new one: such embeddings are not unique, leading to an ambiguity in the reference IQE. However, in this codimension-two setting there are two curvatures associated with S: the curvatures of its tangent and normal bundles. Taking advantage of this fact, I will suggest a possible way to resolve the embedding ambiguity, which at the same time will be seen to incorporate angular momentum into the energy at the quasilocal level. I will analyze the IQE in the following cases: both the spatial and future null infinity limits of a large sphere in asymptotically flat spacetimes; a small sphere shrinking toward a point along either spatial or null directions; and finally, in asymptotically anti-de Sitter spacetimes. The last case reveals a striking similarity between the reference IQE and a certain counterterm energy recently proposed in the context of the conjectured AdS/CFT correspondence.Comment: 54 pages LaTeX, no figures, includes brief summary of results, submitted to Physical Review

Cold atom Clocks and Applications

This paper describes advances in microwave frequency standards using laser-cooled atoms at BNM-SYRTE. First, recent improvements of the $^{133}$Cs and $^{87}$Rb atomic fountains are described. Thanks to the routine use of a cryogenic sapphire oscillator as an ultra-stable local frequency reference, a fountain frequency instability of $1.6\times 10^{-14}\tau^{-1/2}$ where $\tau$ is the measurement time in seconds is measured. The second advance is a powerful method to control the frequency shift due to cold collisions. These two advances lead to a frequency stability of $2\times 10^{-16}$ at $50,000s for the first time for primary standards. In addition, these clocks realize the SI second with an accuracy of$7\times 10^{-16}$, one order of magnitude below that of uncooled devices. In a second part, we describe tests of possible variations of fundamental constants using$^{87}$Rb and$^{133}$Cs fountains. Finally we give an update on the cold atom space clock PHARAO developed in collaboration with CNES. This clock is one of the main instruments of the ACES/ESA mission which is scheduled to fly on board the International Space Station in 2008, enabling a new generation of relativity tests.Comment: 30 pages, 11 figure

POLR3A variants with striatal involvement and extrapyramidal movement disorder

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant

Pion-Nucleon Scattering in a Large-N Sigma Model

We review the large-N_c approach to meson-baryon scattering, including recent interesting developments. We then study pion-nucleon scattering in a particular variant of the linear sigma-model, in which the couplings of the sigma and pi mesons to the nucleon are echoed by couplings to the entire tower of I=J baryons (including the Delta) as dictated by large-N_c group theory. We sum the complete set of multi-loop meson-exchange \pi N --> \pi N and \pi N --> \sigma N Feynman diagrams, to leading order in 1/N_c. The key idea, reviewed in detail, is that large-N_c allows the approximation of LOOP graphs by TREE graphs, so long as the loops contain at least one baryon leg; trees, in turn, can be summed by solving classical equations of motion. We exhibit the resulting partial-wave S-matrix and the rich nucleon and Delta resonance spectrum of this simple model, comparing not only to experiment but also to pion-nucleon scattering in the Skyrme model. The moral is that much of the detailed structure of the meson-baryon S-matrix which hitherto has been uncovered only with skyrmion methods, can also be described by models with explicit baryon fields, thanks to the 1/N_c expansion.Comment: This LaTeX file inputs the ReVTeX macropackage; figures accompany i

Validation of TOI-1221 b: A warm sub-Neptune exhibiting TTVs around a Sun-like star

We present a validation of the long-period ($91.68278^{+0.00032}_{-0.00041}$ days) transiting sub-Neptune planet TOI-1221 b (TIC 349095149.01) around a Sun-like (m$_{\rm V}$=10.5) star. This is one of the few known exoplanets with period >50 days, and belongs to the even smaller subset of which have bright enough hosts for detailed spectroscopic follow-up. We combine TESS light curves and ground-based time-series photometry from PEST (0.3~m) and LCOGT (1.0~m) to analyze the transit signals and rule out nearby stars as potential false positive sources. High-contrast imaging from SOAR and Gemini/Zorro rule out nearby stellar contaminants. Reconnaissance spectroscopy from CHIRON sets a planetary scale upper mass limit on the transiting object (1.1 and 3.5 M$_{\rm Jup}$ at 1$\sigma$ and 3$\sigma$, respectively) and shows no sign of a spectroscopic binary companion. We determine a planetary radius of $R_{\rm p} = 2.91^{+0.13}_{-0.12} R_{\oplus}$, placing it in the sub-Neptune regime. With a stellar insolation of $S = 6.06^{+0.85}_{-0.77}\ S_{\oplus}$, we calculate a moderate equilibrium temperature of $T_{\rm eq} =$ 440 K, assuming no albedo and perfect heat redistribution. We find a false positive probability from TRICERATOPS of FPP $= 0.0014 \pm 0.0003$ as well as other qualitative and quantitative evidence to support the statistical validation of TOI-1221 b. We find significant evidence (>$5\sigma$) of oscillatory transit timing variations, likely indicative of an additional non-transiting planet.Comment: 17 pages, 9 figures, 4 table

Genome-Wide Tissue-Specific Occupancy of the Hox Protein Ultrabithorax and Hox Cofactor Homothorax in Drosophila

The Hox genes are responsible for generating morphological diversity along the anterior-posterior axis during animal development. The Drosophila Hox gene Ultrabithorax (Ubx), for example, is required for specifying the identity of the third thoracic (T3) segment of the adult, which includes the dorsal haltere, an appendage required for flight, and the ventral T3 leg. Ubx mutants show homeotic transformations of the T3 leg towards the identity of the T2 leg and the haltere towards the wing. All Hox genes, including Ubx, encode homeodomain containing transcription factors, raising the question of what target genes Ubx regulates to generate these adult structures. To address this question, we carried out whole genome ChIP-chip studies to identify all of the Ubx bound regions in the haltere and T3 leg imaginal discs, which are the precursors to these adult structures. In addition, we used ChIP-chip to identify the sites bound by the Hox cofactor, Homothorax (Hth). In contrast to previous ChIP-chip studies carried out in Drosophila embryos, these binding studies reveal that there is a remarkable amount of tissue- and transcription factor-specific binding. Analyses of the putative target genes bound and regulated by these factors suggest that Ubx regulates many downstream transcription factors and developmental pathways in the haltere and T3 leg. Finally, we discovered additional DNA sequence motifs that in some cases are specific for individual data sets, arguing that Ubx and/or Hth work together with many regionally expressed transcription factors to execute their functions. Together, these data provide the first whole-genome analysis of the binding sites and target genes regulated by Ubx to specify the morphologies of the adult T3 segment of the fly

Establishing a core outcome set for peritoneal dialysis : report of the SONG-PD (standardized outcomes in nephrology-peritoneal dialysis) consensus workshop

Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD

Neutrino masses: From fantasy to facts

Theory suggests the existence of neutrino masses, but little more. Facts are coming close to reveal our fantasy: solar and atmospheric neutrino data strongly indicate the need for neutrino conversions, while LSND provides an intriguing hint. The simplest ways to reconcile these data in terms of neutrino oscillations invoke a light sterile neutrino in addition to the three active ones. Out of the four neutrinos, two are maximally-mixed and lie at the LSND scale, while the others are at the solar mass scale. These schemes can be distinguished at neutral-current-sensitive solar & atmospheric neutrino experiments. I discuss the simplest theoretical scenarios, where the lightness of the sterile neutrino, the nearly maximal atmospheric neutrino mixing, and the generation of $\Delta {m^2}_\odot$ & $\Delta {m^2}_{atm}$ all follow naturally from the assumed lepton-number symmetry and its breaking. Although the most likely interpretation of the present data is in terms of neutrino-mass-induced oscillations, one still has room for alternative explanations, such as flavour changing neutrino interactions, with no need for neutrino mass or mixing. Such flavour violating transitions arise in theories with strictly massless neutrinos, and may lead to other sizeable flavour non-conservation effects, such as $\mu \to e + \gamma$, $\mu-e$ conversion in nuclei, unaccompanied by neutrino-less double beta decay.Comment: 33 pages, latex, 16 figures. Invited Talk at Ioannina Conference, Symmetries in Intermediate High Energy Physics and its Applications, Oct. 1998, to be published by Springer Tracts in Modern Physics. Festschrift in Honour of John Vergados' 60th Birthda