1,119 research outputs found
Search algorithms as a framework for the optimization of drug combinations
Combination therapies are often needed for effective clinical outcomes in the
management of complex diseases, but presently they are generally based on
empirical clinical experience. Here we suggest a novel application of search
algorithms, originally developed for digital communication, modified to
optimize combinations of therapeutic interventions. In biological experiments
measuring the restoration of the decline with age in heart function and
exercise capacity in Drosophila melanogaster, we found that search algorithms
correctly identified optimal combinations of four drugs with only one third of
the tests performed in a fully factorial search. In experiments identifying
combinations of three doses of up to six drugs for selective killing of human
cancer cells, search algorithms resulted in a highly significant enrichment of
selective combinations compared with random searches. In simulations using a
network model of cell death, we found that the search algorithms identified the
optimal combinations of 6-9 interventions in 80-90% of tests, compared with
15-30% for an equivalent random search. These findings suggest that modified
search algorithms from information theory have the potential to enhance the
discovery of novel therapeutic drug combinations. This report also helps to
frame a biomedical problem that will benefit from an interdisciplinary effort
and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio
Perturbative quantum gravity with the Immirzi parameter
We study perturbative quantum gravity in the first-order tetrad formalism.
The lowest order action corresponds to Einstein-Cartan plus a parity-odd term,
and is known in the literature as the Holst action. The coupling constant of
the parity-odd term can be identified with the Immirzi parameter of loop
quantum gravity. We compute the quantum effective action in the one-loop
expansion. As in the metric second-order formulation, we find that in the case
of pure gravity the theory is on-shell finite, and the running of Newton's
constant and the Immirzi parameter is inessential. In the presence of fermions,
the situation changes in two fundamental aspects. First, non-renormalizable
logarithmic divergences appear, as usual. Second, the Immirzi parameter becomes
a priori observable, and we find that it is renormalized by a four-fermion
interaction generated by radiative corrections. We compute its beta function
and discuss possible implications. The sign of the beta function depends on
whether the Immirzi parameter is larger or smaller than one in absolute value,
and the values plus or minus one are UV fixed-points (we work in Euclidean
signature). Finally, we find that the Holst action is stable with respect to
radiative corrections in the case of minimal coupling, up to higher order
non-renormalizable interactions.Comment: v2 minor amendment
Physics Opportunities of e+e- Linear Colliders
We describe the anticipated experimental program of an e+e- linear collider
in the energy range 500 GeV -- 1.5 TeV. We begin with a description of current
collider designs and the expected experimental environment. We then discuss
precision studies of the W boson and top quark. Finally, we review the range of
models proposed to explain the physics of electroweak symmetry breaking and
show, for each case, the central role that the linear collider experiments will
play in elucidating this physics. (to appear in Annual Reviews of Nuclear and
Particle Science)Comment: 93 pages, latex + 23 figures; typos corrections + 1 reference adde
Effect of inhomogeneity of the Universe on a gravitationally bound local system: A no-go result for explaining the secular increase in the astronomical unit
We will investigate the influence of the inhomogeneity of the universe,
especially that of the Lema{\^i}tre-Tolman-Bondi (LTB) model, on a
gravitationally bound local system such as the solar system. We concentrate on
the dynamical perturbation to the planetary motion and derive the leading order
effect generated from the LTB model. It will be shown that there appear not
only a well-known cosmological effect arisen from the homogeneous and isotropic
model, such as the Robertson-Walker (RW) model, but also the additional terms
due to the radial inhomogeneity of the LTB model. We will also apply the
obtained results to the problem of secular increase in the astronomical unit,
reported by Krasinsky and Brumberg (2004), and imply that the inhomogeneity of
the universe cannot have a significant effect for explaining the observed
.Comment: 12 pages, no figure, accepted for publication in Journal of
Astrophysics and Astronom
Effects of Thyroxine Exposure on Osteogenesis in Mouse Calvarial Pre-Osteoblasts
The incidence of craniosynostosis is one in every 1,800-2500 births. The gene-environment model proposes that if a genetic predisposition is coupled with environmental exposures, the effects can be multiplicative resulting in severely abnormal phenotypes. At present, very little is known about the role of gene-environment interactions in modulating craniosynostosis phenotypes, but prior evidence suggests a role for endocrine factors. Here we provide a report of the effects of thyroid hormone exposure on murine calvaria cells. Murine derived calvaria cells were exposed to critical doses of pharmaceutical thyroxine and analyzed after 3 and 7 days of treatment. Endpoint assays were designed to determine the effects of the hormone exposure on markers of osteogenesis and included, proliferation assay, quantitative ALP activity assay, targeted qPCR for mRNA expression of Runx2, Alp, Ocn, and Twist1, genechip array for 28,853 targets, and targeted osteogenic microarray with qPCR confirmations. Exposure to thyroxine stimulated the cells to express ALP in a dose dependent manner. There were no patterns of difference observed for proliferation. Targeted RNA expression data confirmed expression increases for Alp and Ocn at 7 days in culture. The genechip array suggests substantive expression differences for 46 gene targets and the targeted osteogenesis microarray indicated 23 targets with substantive differences. 11 gene targets were chosen for qPCR confirmation because of their known association with bone or craniosynostosis (Col2a1, Dmp1, Fgf1, 2, Igf1, Mmp9, Phex, Tnf, Htra1, Por, and Dcn). We confirmed substantive increases in mRNA for Phex, FGF1, 2, Tnf, Dmp1, Htra1, Por, Igf1 and Mmp9, and substantive decreases for Dcn. It appears thyroid hormone may exert its effects through increasing osteogenesis. Targets isolated suggest a possible interaction for those gene products associated with calvarial suture growth and homeostasis as well as craniosynostosis. © 2013 Cray et al
Estimating Sensitivity of Laboratory Testing for Influenza in Canada through Modelling
Background: The weekly proportion of laboratory tests that are positive for influenza is used in public health surveillance systems to identify periods of influenza activity. We aimed to estimate the sensitivity of influenza testing in Canada based on results of a national respiratory virus surveillance system. Methods and Findings: The weekly number of influenza-negative tests from 1999 to 2006 was modelled as a function of laboratory-confirmed positive tests for influenza, respiratory syncytial virus (RSV), adenovirus and parainfluenza viruses, seasonality, and trend using Poisson regression. Sensitivity was calculated as the number of influenza positive tests divided by the number of influenza positive tests plus the model-estimated number of false negative tests. The sensitivity of influenza testing was estimated to be 33 % (95%CI 32–34%), varying from 30–40 % depending on the season and region. Conclusions: The estimated sensitivity of influenza tests reported to this national laboratory surveillance system is considerably less than reported test characteristics for most laboratory tests. A number of factors may explain this difference, including sample quality and specimen procurement issues as well as test characteristics. Improved diagnosis would permit better estimation of the burden of influenza
Liposomal Co-Entrapment of CD40mAb Induces Enhanced IgG Responses against Bacterial Polysaccharide and Protein
Background
Antibody against CD40 is effective in enhancing immune responses to vaccines when chemically conjugated to the vaccine antigen. Unfortunately the requirement for chemical conjugation presents some difficulties in vaccine production and quality control which are compounded when multivalent vaccines are required. We explore here an alternative to chemical conjugation, involving the co-encapsulation of CD40 antibody and antigens in liposomal vehicles.
Methodology/Principal Findings
Anti-mouse CD40 mAb or isotype control mAb were co-entrapped individually in cationic liposomal vehicles with pneumococcal polysaccharides or diphtheria and tetanus toxoids. Retention of CD40 binding activity upon liposomal entrapment was assessed by ELISA and flow cytometry. After subcutaneous immunization of BALB/c female mice, anti-polysaccharide and DT/TT responses were measured by ELISA. Simple co-encapsulation of CD40 antibody allowed for the retention of CD40 binding on the liposome surface, and also produced vaccines with enhanced imunogenicity. Antibody responses against both co-entrapped protein in the form of tetanus toxoid, and Streptococcus pneumoniae capsular polysaccharide, were enhanced by co-encapsulation with CD40 antibody. Surprisingly, liposomal encapsulation also appeared to decrease the toxicity of high doses of CD40 antibody as assessed by the degree of splenomegaly induced.
Conclusions/Significance
Liposomal co-encapsulation with CD40 antibody may represent a practical means of producing more immunogenic multivalent vaccines and inducing IgG responses against polysaccharides without the need for conjugation
Performance of an Influenza Rapid Test in Children in a Primary Healthcare Setting in Nicaragua
Background: Influenza is major public health threat worldwide, yet the diagnostic accuracy of rapid tests in developing country settings is not well described. Methodology/Principal Findings: To investigate the diagnostic accuracy of the QuickVue Influenza A+B test in a primary care setting in a developing country, we performed a prospective study of diagnostic accuracy of the QuickVue Influenza A+B test in comparison to reverse transcriptase-polymerase chain reaction (RT-PCR) in a primary healthcare setting in children aged 2 to 12 years in Managua, Nicaragua. The sensitivity and specificity of the QuickVue test compared to RT-PCR were 68.5 % (95 % CI 63.4, 73.3) and 98.1 % (95 % CI 96.9, 98.9), respectively, for children with a fever or history of a fever and cough and/or sore throat. Test performance was found to be lower on the first day that symptoms developed in comparison to test performance on days two or three of illness. Conclusions/Significance: Our study found that the QuickVue Influenza A+B test performed as well in a developing countr
The Cosmological Constant
This is a review of the physics and cosmology of the cosmological constant.
Focusing on recent developments, I present a pedagogical overview of cosmology
in the presence of a cosmological constant, observational constraints on its
magnitude, and the physics of a small (and potentially nonzero) vacuum energy.Comment: 50 pages. Submitted to Living Reviews in Relativity
(http://www.livingreviews.org/), December 199
Is a Calorie Really a Calorie? Metabolic Advantage of Low-Carbohydrate Diets
The first law of thermodynamics dictates that body mass remains constant when caloric intake equals caloric expenditure. It should be noted, however, that different diets lead to different biochemical pathways that are not equivalent when correctly compared through the laws of thermodynamics. It is inappropriate to assume that the only thing that counts in terms of food consumption and energy balance is the intake of dietary calories and weight storage. Well-controlled studies suggest that calorie content may not be as predictive of fat loss as is reduced carbohydrate consumption. Biologically speaking, a calorie is certainly not a calorie. The ideal weight loss diet, if it even exists, remains to be determined, but a high-carbohydrate/low-protein diet may be unsatisfactory for many obese individuals
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