329 research outputs found
Proof techniques for CCS
Proofs of observational equivalence of behaviour expressions in
Milner's Calculus of Communicating Systems can be quite lengthy,
and as larger and more practical systems of agents are considered
the need for shorter proof techniques becomes more important. In
this thesis a number of results about the calculus are proved
which give rise to give more natural techniques. Three
principal areas of research are presented:(i) A study of strong confluence and determinacy is made,
extending Hilner's work to the whole calculus - the
appropriate modifications to take value-passing into account
are motivated and defined, and a strong confluence theorem
is proved. It is shown that a useful subcalculus of CCS is
strongly confluent.(ii) An investigation into criteria for uniqueness of solution of
equations pf the form b = Fib] is performed. To do this a
concept of derivations of an agent A "causing" derivations
of FlAl is defined; using this, conditions are imposed on F
which imply uniqueness, and a study follows of how these
conditions relate to the structure of F.(iii) By using an alternative, stronger, definition of
observational equivalence as a maximal fixed point it is
found that equivalences can be demonstrated by constructing
bisimulations between agents, and results leading to an
algorithm for such constructions are presented. Also, using
this alternative definition a weaker form of confluence can
be defined very easily, and this is investigated.The theoretical material in this thesis is supplemented by
examples demonstrating how the results proved can be applied to
give proof techniques for use within the calculus
LoCuSS: A Comparison of Sunyaev-Zel'dovich Effect and Gravitational Lensing Measurements of Galaxy Clusters
We present the first measurement of the relationship between the
Sunyaev-Zel'dovich effect signal and the mass of galaxy clusters that uses
gravitational lensing to measure cluster mass, based on 14 X-ray luminous
clusters at z~0.2 from the Local Cluster Substructure Survey. We measure the
integrated Compton y-parameter, Y, and total projected mass of the clusters
(M_GL) within a projected clustercentric radius of 350 kpc, corresponding to
mean overdensities of 4000-8000 relative to the critical density. We find
self-similar scaling between M_GL and Y, with a scatter in mass at fixed Y of
32%. This scatter exceeds that predicted from numerical cluster simulations,
however, it is smaller than comparable measurements of the scatter in mass at
fixed T_X. We also find no evidence of segregation in Y between disturbed and
undisturbed clusters, as had been seen with T_X on the same physical scales. We
compare our scaling relation to the Bonamente et al. relation based on mass
measurements that assume hydrostatic equilibrium, finding no evidence for a
hydrostatic mass bias in cluster cores (M_GL = 0.98+/-0.13 M_HSE), consistent
with both predictions from numerical simulations and lensing/X-ray-based
measurements of mass-observable scaling relations at larger radii. Overall our
results suggest that the Sunyaev-Zel'dovich effect may be less sensitive than
X-ray observations to the details of cluster physics in cluster cores.Comment: Minor changes to match published version: 2009 ApJL 701:114-11
Human marginal zone B cell development from early T2 progenitors.
B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health
Can a “state of the art” chemistry transport model simulate Amazonian tropospheric chemistry?
We present an evaluation of a nested high-resolution Goddard Earth Observing System (GEOS)-Chem chemistry transport model simulation of tropospheric chemistry over tropical South America. The model has been constrained with two isoprene emission inventories: (1) the canopy-scale Model of Emissions of Gases and Aerosols from Nature (MEGAN) and (2) a leaf-scale algorithm coupled to the Lund-Potsdam-Jena General Ecosystem Simulator (LPJ-GUESS) dynamic vegetation model, and the model has been run using two different chemical mechanisms that contain alternative treatments of isoprene photo-oxidation. Large differences of up to 100 Tg C yr^(−1) exist between the isoprene emissions predicted by each inventory, with MEGAN emissions generally higher. Based on our simulations we estimate that tropical South America (30–85°W, 14°N–25°S) contributes about 15–35% of total global isoprene emissions. We have quantified the model sensitivity to changes in isoprene emissions, chemistry, boundary layer mixing, and soil NO_x emissions using ground-based and airborne observations. We find GEOS-Chem has difficulty reproducing several observed chemical species; typically hydroxyl concentrations are underestimated, whilst mixing ratios of isoprene and its oxidation products are overestimated. The magnitude of model formaldehyde (HCHO) columns are most sensitive to the choice of chemical mechanism and isoprene emission inventory. We find GEOS-Chem exhibits a significant positive bias (10–100%) when compared with HCHO columns from the Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) and Ozone Monitoring Instrument (OMI) for the study year 2006. Simulations that use the more detailed chemical mechanism and/or lowest isoprene emissions provide the best agreement to the satellite data, since they result in lower-HCHO columns
Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses; estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1; further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12; consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12
Parameterization Effects in the analysis of AMI Sunyaev-Zel'dovich Observations
Most Sunyaev--Zel'dovich (SZ) and X-ray analyses of galaxy clusters try to
constrain the cluster total mass and/or gas mass using parameterised models and
assumptions of spherical symmetry and hydrostatic equilibrium. By numerically
exploring the probability distributions of the cluster parameters given the
simulated interferometric SZ data in the context of Bayesian methods, and
assuming a beta-model for the electron number density we investigate the
capability of this model and analysis to return the simulated cluster input
quantities via three rameterisations. In parameterisation I we assume that the
T is an input parameter. We find that parameterisation I can hardly constrain
the cluster parameters. We then investigate parameterisations II and III in
which fg(r200) replaces temperature as a main variable. In parameterisation II
we relate M_T(r200) and T assuming hydrostatic equilibrium. We find that
parameterisation II can constrain the cluster physical parameters but the
temperature estimate is biased low. In parameterisation III, the virial theorem
replaces the hydrostatic equilibrium assumption. We find that parameterisation
III results in unbiased estimates of the cluster properties. We generate a
second simulated cluster using a generalised NFW (GNFW) pressure profile and
analyse it with an entropy based model to take into account the temperature
gradient in our analysis and improve the cluster gas density distribution. This
model also constrains the cluster physical parameters and the results show a
radial decline in the gas temperature as expected. The mean cluster total mass
estimates are also within 1 sigma from the simulated cluster true values.
However, we find that for at least interferometric SZ analysis in practice at
the present time, there is no differences in the AMI visibilities between the
two models. This may of course change as the instruments improve.Comment: 19 pages, 13 tables, 24 figure
The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects
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