Introducing the microbiome into Precision Medicine

© The Author(s), 2016. This is the author's version of the work and is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Trends in Pharmacological Sciences 38 (2017): 81-91, doi:10.1016/j.tips.2016.10.001.Understanding how individual people respond to medical therapy is a key facet of improving the odds ratio that interventions will have a positive impact. Reducing the non-responder rate for an intervention or reducing complications associated with a particular treatment or surgery is the next stage of medical advance. The Precision Medicine Initiative, launched in January 2015, set the stage for enhanced collaboration between researchers and medical professionals to develop next-generation techniques to aid patient treatment and recovery, and increased the opportunities for impactful pre-emptive care. The microbiome plays a crucial role in health and disease, as it influences endocrinology, physiology, and even neurology, altering the outcome of many different disease states, and it augments drug responses and tolerance. We review the implications of the microbiome on precision health initiatives and highlight excellent examples, whereby precision microbiome health has been implemented.2017-11-0

Fragmentation Phase Transition in Atomic Clusters II - Coulomb Explosion of Metal Clusters -

We discuss the role and the treatment of polarization effects in many-body systems of charged conducting clusters and apply this to the statistical fragmentation of Na-clusters. We see a first order microcanonical phase transition in the fragmentation of $Na^{Z+}_{70}$ for Z=0 to 8. We can distinguish two fragmentation phases, namely evaporation of large particles from a large residue and a complete decay into small fragments only. Charging the cluster shifts the transition to lower excitation energies and forces the transition to disappear for charges higher than Z=8. At very high charges the fragmentation phase transition no longer occurs because the cluster Coulomb-explodes into small fragments even at excitation energy $\epsilon^* = 0$.Comment: 19 text pages +18 *.eps figures, my e-mail adress: [email protected] submitted to Z. Phys.

Contribution of Unresolved Point Sources to the Diffuse X-ray Background below 1 keV

We present here the analysis of X-rays point sources detected in several observations available in the XMM-Newton public archive. We focused, in particular, on energies below 1 keV, which are of particular relevance to the understanding of the Diffuse X-ray Background. The average field of all the exposures is 0.09 deg^-2. We reached an average flux sensitivity of 5.8x10^-16 erg s^-1 cm^-2 in the soft band (0.5-2.0 keV) and 2.5x10^-16 erg s^-1 cm^-2 in the very soft band (0.4-0.6 keV). In this paper we discuss the logN-logS results, the contribution to the integrated X-ray sky flux, and the properties of the cumulative spectrum from all sources. In particular, we found an excess flux at around 0.5 keV in the composite spectrum of faint sources. The excess seems to be a general property of all the fields observed suggesting an additional class of weak sources is contributing to the X-ray emission at these energies. Combining our results with previous investigations we have also quantified the contribution of the individual components of the diffuse X-ray Background in the 3/4 keV band.Comment: Accepted for publication in ApJ; 27 pages, 8 figure

Spatial and temporal characterization of a Bessel beam produced using a conical mirror

We experimentally analyze a Bessel beam produced with a conical mirror, paying particular attention to its superluminal and diffraction-free properties. We spatially characterized the beam in the radial and on-axis dimensions, and verified that the central peak does not spread over a propagation distance of 73 cm. In addition, we measured the superluminal phase and group velocities of the beam in free space. Both spatial and temporal measurements show good agreement with the theoretical predictions.Comment: 5 pages, 6 figure

Multigenome DNA sequence conservation identifies Hox cis-regulatory elements

To learn how well ungapped sequence comparisons of multiple species can predict cis-regulatory elements in Caenorhabditis elegans, we made such predictions across the large, complex ceh-13/lin-39 locus and tested them transgenically. We also examined how prediction quality varied with different genomes and parameters in our comparisons. Specifically, we sequenced ∼0.5% of the C. brenneri and C. sp. 3 PS1010 genomes, and compared five Caenorhabditis genomes (C. elegans, C. briggsae, C. brenneri, C. remanei, and C. sp. 3 PS1010) to find regulatory elements in 22.8 kb of noncoding sequence from the ceh-13/lin-39 Hox subcluster. We developed the MUSSA program to find ungapped DNA sequences with N-way transitive conservation, applied it to the ceh-13/lin-39 locus, and transgenically assayed 21 regions with both high and low degrees of conservation. This identified 10 functional regulatory elements whose activities matched known ceh-13/lin-39 expression, with 100% specificity and a 77% recovery rate. One element was so well conserved that a similar mouse Hox cluster sequence recapitulated the native nematode expression pattern when tested in worms. Our findings suggest that ungapped sequence comparisons can predict regulatory elements genome-wide

Crackling Noise, Power Spectra and Disorder Induced Critical Scaling

Crackling noise is observed in many disordered non-equilibrium systems in response to slowly changing external conditions. Examples range from Barkhausen noise in magnets to acoustic emission in martensites to earthquakes. Using the non-equilibrium random field Ising model, we derive universal scaling predictions for the dependence of the associated power spectra on the disorder and field sweep rate, near an underlying disorder-induced non-equilibrium critical point. Our theory applies to certain systems in which the crackling noise results from avalanche-like response to a (slowly) increasing external driving force, and is characterized by a broad power law scaling regime of the power spectra. We compute the critical exponents and discuss the relevance of the results to experiments.Comment: 27 Latex Pages, 14 eps figure

Cost-Effectiveness of Interferon Beta-1a, Interferon Beta-1b, and Glatiramer Acetate in Newly Diagnosed Non-primary Progressive Multiple Sclerosis

AbstractObjectiveTo perform a cost-effectiveness analysis of three immunomodulatory treatments for newly diagnosed nonprimary progressive MS: interferon beta-1a, interferon beta-1b, and glatiramer acetate.MethodsWe developed a state-transition model to estimate the health effects and costs associated with interferon beta-1a, interferon beta-1b, glatiramer acetate, and no treatment for hypothetical cohorts of men and women with non-primary progressive MS. We used the Expanded Disability Status Scale as the measure of disability and included both relapses and disease progression in the model. We evaluated treatment strategies assuming a 10-year treatment duration using the societal perspective. We elicited preferences for disability and treatment states using standard-gamble questions and modeled the disutility associated with treatment administration and side effects explicitly. Main outcome measures were net gains in quality-adjusted life expectancy and incremental cost-effectiveness ratios in dollars per quality-adjusted life year (QALY) gained.ResultsFor treatment duration of 10 years for newly diagnosed non-primary progressive MS, interferon beta-1a yielded the largest gain in quality-adjusted life expectancy with an incremental cost-effectiveness ratio of $2,200,000/QALY for women and$1,800,000/QALY for men, compared with no treatment. For a 5-year treatment duration, a “no treatment” strategy yielded more quality-adjusted life years than any of the treatment strategies. Cost-effectiveness ratios were similar for all three immunomodulatory treatments evaluated.ConclusionsCost-effectiveness results for all three immunomodulatory treatments for MS were unfavorable in the simulated study population under a wide range of assumptions. For treatment duration less than or equal to 5 years, expected benefits of treatment may not outweigh disutility associated with side effects and treatment discomfort

Physical Structure and Nature of Supernova Remnants in M101

Supernova remnant (SNR) candidates in the giant spiral galaxy M101 have been previously identified from ground-based H-alpha and [SII] images. We have used archival Hubble Space Telescope (HST) H-alpha and broad-band images as well as stellar photometry of 55 SNR candidates to examine their physical structure, interstellar environment, and underlying stellar population. We have also obtained high-dispersion echelle spectra to search for shocked high-velocity gas in 18 SNR candidates, and identified X-ray counterparts to SNR candidates using data from archival observations made by the Chandra X-ray Observatory. Twenty-one of these 55 SNR candidates studied have X-ray counterparts, although one of them is a known ultra-luminous X-ray source. The multi-wavelength information has been used to assess the nature of each SNR candidate. We find that within this limited sample, ~16% are likely remnants of Type Ia SNe and ~45% are remnants of core-collapse SNe. In addition, about ~36% are large candidates which we suggest are either superbubbles or OB/HII complexes. Existing radio observations are not sensitive enough to detect the non-thermal emission from these SNR candidates. Several radio sources are coincident with X-ray sources, but they are associated with either giant HII regions in M101 or background galaxies. The archival HST H-alpha images do not cover the entire galaxy and thus prevents a complete study of M101. Furthermore, the lack of HST [SII] images precludes searches for small SNR candidates which could not be identified by ground-based observations. Such high-resolution images are needed in order to obtain a complete census of SNRs in M101 for a comprehensive investigation of the distribution, population, and rates of SNe in this galaxy.Comment: 37 pages, 4 Tables, 7 Figures, accepted for publication in the Astronomical Journa

Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes.

We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-β (Aβ) plaque pathology and astrogliosis in the male amyloid precursor protein (APP)SWE /presenilin 1 (PS1)ΔE9 transgenic model of Aβ amyloidosis. We now show that in an independent, aggressive APPSWE/PS1L166P (APPPS1-21) mouse model of Aβ amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in Aβ pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male mice, not in the brains of female mice. Furthermore, ABX treatment lead to alterations in levels of selected microglial expressed transcripts indicative of the "M0" homeostatic state in male but not in female mice. Finally, we found that transplants of fecal microbiota from age-matched APPPS1-21 male mice into ABX-treated APPPS1-21 male restores the gut microbiome and partially restores Aβ pathology and microglial morphology, thus demonstrating a causal role of the microbiome in the modulation of Aβ amyloidosis and microglial physiology in mouse models of Aβ amyloidosis

Fast spectroscopic variations on rapidly-rotating, cool dwarfs. 3: Masses of circumstellar absorbing clouds on AB Doradus

New time-resolved H alpha, Ca II H and K and Mg II h and k spectra of the rapidly-rotating K0 dwarf star AB Doradus (= HD 36705). The transient absorption features seen in the H alpha line are also present in the Ca II and Mg II resonance lines. New techniques are developed for measuring the average strength of the line absorption along lines of sight intersecting the cloud. These techniques also give a measure of the projected cloud area. The strength of the resonance line absorption provides useful new constraints on the column densities, projected surface areas, temperatures and internal turbulent velocity dispersions of the circumstellar clouds producing the absorption features. At any given time the star appears to be surrounded by at least 6 to 10 clouds with masses in the range 2 to 6 x 10(exp 17) g. The clouds appear to have turbulent internal velocity dispersions of order 3 to 20 km/s, comparable with the random velocities of discrete filamentary structures in solar quiescent prominences. Night-to-night changes in the amount of Ca II resonance line absorption can be explained by changes in the amplitude of turbulent motions in the clouds. The corresponding changes in the total energy of the internal motions are of order 10(exp 29) erg per cloud. Changes of this magnitude could easily be activated by the frequent energetic (approximately 10(exp 34) erg) x ray flares seen on this star