6,773 research outputs found
sscMap: An extensible Java application for connecting small-molecule drugs using gene-expression signatures
Background: Connectivity mapping is a process to recognize novel
pharmacological and toxicological properties in small molecules by comparing
their gene expression signatures with others in a database. A simple and robust
method for connectivity mapping with increased specificity and sensitivity was
recently developed, and its utility demonstrated using experimentally derived
gene signatures.
Results: This paper introduces sscMap (statistically significant connections'
map), a Java application designed to undertake connectivity mapping tasks using
the recently published method. The software is bundled with a default
collection of reference gene-expression profiles based on the publicly
available dataset from the Broad Institute Connectivity Map 02, which includes
data from over 7000 Affymetrix microarrays, for over 1000 small-molecule
compounds, and 6100 treatment instances in 5 human cell lines. In addition, the
application allows users to add their custom collections of reference profiles
and is applicable to a wide range of other 'omics technologies.
Conclusions: The utility of sscMap is two fold. First, it serves to make
statistically significant connections between a user-supplied gene signature
and the 6100 core reference profiles based on the Broad Institute expanded
dataset. Second, it allows users to apply the same improved method to
custom-built reference profiles which can be added to the database for future
referencing. The software can be freely downloaded from
http://purl.oclc.org/NET/sscMapComment: 3 pages, 1 table, 1 eps figur
A visual method for high-dimensional data cluster exploration
Visualization is helpful for clustering high dimensional data. The goals of visualization in data mining are exploration, confirmation and presentation of the clustering results. However, the most of visual techniques developed for cluster analysis are primarily focused on cluster presentation rather than cluster exploration. Several techniques have been proposed to explore cluster information by visualization, but most of them depend heavily on the individual user's experience. Inevitably, this incurs subjectivity and randomness in the clustering process. In this paper, we employ the statistical features of datasets as predictions to estimate the number of clusters by a visual technique called HOV3. This approach mitigates the problem of the randomness and subjectivity of the user during the process of cluster exploration by other visual techniques. As a result, our approach provides an effective visual method for cluster exploration. © 2009 Springer-Verlag Berlin Heidelberg
A simple and robust method for connecting small-molecule drugs using gene-expression signatures
Interaction of a drug or chemical with a biological system can result in a
gene-expression profile or signature characteristic of the event. Using a
suitably robust algorithm these signatures can potentially be used to connect
molecules with similar pharmacological or toxicological properties. The
Connectivity Map was a novel concept and innovative tool first introduced by
Lamb et al to connect small molecules, genes, and diseases using genomic
signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the
Connectivity Map had some limitations, particularly there was no effective
safeguard against false connections if the observed connections were considered
on an individual-by-individual basis. Further when several connections to the
same small-molecule compound were viewed as a set, the implicit null hypothesis
tested was not the most relevant one for the discovery of real connections.
Here we propose a simple and robust method for constructing the reference
gene-expression profiles and a new connection scoring scheme, which importantly
allows the valuation of statistical significance of all the connections
observed. We tested the new method with the two example gene-signatures (HDAC
inhibitors and Estrogens) used by Lamb et al and also a new gene signature of
immunosuppressive drugs. Our testing with this new method shows that it
achieves a higher level of specificity and sensitivity than the original
method. For example, our method successfully identified raloxifene and
tamoxifen as having significant anti-estrogen effects, while Lamb et al's
Connectivity Map failed to identify these. With these properties our new method
has potential use in drug development for the recognition of pharmacological
and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a
ZIP fil
AtPAP2 modulates the import of the small subunit of Rubisco into chloroplasts
published_or_final_versio
An epidemiologic study of early biologic effects of benzene in Chinese workers.
Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cells levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cells levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colony-stimulating factor, tissue necrosis factor-alpha) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and N phi variants, which arise from gene inactivation. The NN (but not N phi) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean +/- SD, 13.9 +/- 8.4 mutants per million cells versus 7.4 +/- 5.2 per million cells, (respectively; p = 0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans
Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice
<div><p>Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.</p></div
Does the risk of cerebral palsy increase or decrease with increasing gestational age?
BACKGROUND: It is generally accepted that the risk of cerebral palsy decreases with increasing gestational age of live born infants. However, recent studies have shown that cerebral palsy often has prenatal antecedents including congenital malformations, vascular insults and maternal infection. Cerebral palsy is therefore better viewed as occurring among fetuses, rather than among infants. We explored the epidemiologic implications of this change in perspective. METHODS: We used recently published data from Shiga Prefecture, Japan and from North-East England to examine the pattern of gestational age-specific rates of cerebral palsy under these alternative perspectives. We first calculated gestational age-specific rates of cerebral palsy as per convention, by dividing the number of cases of cerebral palsy identified among live births within any gestational age category by the number of live births in that gestational age category. Under the alternative formulation, we calculated gestational age-specific rates of cerebral palsy by dividing the number of cases of cerebral palsy identified among live births within any gestational age category by the number of fetuses who were at risk of being born at that gestation and being afflicted with cerebral palsy. RESULTS: Under the conventional formulation, cerebral palsy rates decreased with increasing gestational age from 63.9 per 1,000 live births at <28 weeks gestation to 0.9 per 1,000 live births at 37 or more weeks gestation. When fetuses were viewed as potential candidates for cerebral palsy, cerebral palsy rates increased with increasing gestational age from 0.08 per 1,000 fetuses at risk at <28 weeks gestation to 0.9 per 1,000 fetuses at risk at 37 or more weeks gestation. CONCLUSIONS: The fetuses-at-risk approach is the appropriate epidemiologic formulation for calculating the gestational age-specific rate of cerebral palsy from a causal perspective. It shows that the risk of cerebral palsy increases as gestational duration increases. This compelling view of cerebral palsy risk may help refocus research aimed at understanding and preventing cerebral palsy
Exoplanet phase curves: observations and theory
Phase curves are the best technique to probe the three dimensional structure
of exoplanets' atmospheres. In this chapter we first review current exoplanets
phase curve observations and the particular challenges they face. We then
describe the different physical mechanisms shaping the atmospheric phase curves
of highly irradiated tidally locked exoplanets. Finally, we discuss the
potential for future missions to further advance our understanding of these new
worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been
updated with new values for WASP-103b and WASP-18b. Contains a table
sumarizing phase curve observation
Sign-reversal of the in-plane resistivity anisotropy in hole-doped iron pnictides
The in-plane anisotropy of the electrical resistivity across the coupled
orthorhombic and magnetic transitions of the iron pnictides has been
extensively studied in the parent and electron-doped compounds. All these
studies universally show that the resistivity across the long
orthorhombic axis - along which the spins couple antiferromagnetically
below the magnetic transition temperature - is smaller than the resistivity
of the short orthorhombic axis , i. e. .
Here we report that in the hole-doped compounds
BaKFeAs, as the doping level increases, the
resistivity anisotropy initially becomes vanishingly small, and eventually
changes sign for sufficiently large doping, i. e. . This
observation is in agreement with a recent theoretical prediction that considers
the anisotropic scattering of electrons by spin-fluctuations in the
orthorhombic/nematic state.Comment: This paper has been replaced by the new version offering new
explanation of the experimental results first reported her
Metabolic effects of diets differing in glycaemic index depend on age and endogenous GIP
Aims/hypothesis
High- vs low-glycaemic index (GI) diets unfavourably affect body fat mass and metabolic markers in rodents. Different effects of these diets could be age-dependent, as well as mediated, in part, by carbohydrate-induced stimulation of glucose-dependent insulinotrophic polypeptide (GIP) signalling.
Methods
Young-adult (16 weeks) and aged (44 weeks) male wild-type (C57BL/6J) and GIP-receptor knockout (Gipr −/− ) mice were exposed to otherwise identical high-carbohydrate diets differing only in GI (20–26 weeks of intervention, n = 8–10 per group). Diet-induced changes in body fat distribution, liver fat, locomotor activity, markers of insulin sensitivity and substrate oxidation were investigated, as well as changes in the gene expression of anorexigenic and orexigenic hypothalamic factors related to food intake.
Results
Body weight significantly increased in young-adult high- vs low-GI fed mice (two-way ANOVA, p < 0.001), regardless of the Gipr genotype. The high-GI diet in young-adult mice also led to significantly increased fat mass and changes in metabolic markers that indicate reduced insulin sensitivity. Even though body fat mass also slightly increased in high- vs low-GI fed aged wild-type mice (p < 0.05), there were no significant changes in body weight and estimated insulin sensitivity in these animals. However, aged Gipr −/− vs wild-type mice on high-GI diet showed significantly lower cumulative net energy intake, increased locomotor activity and improved markers of insulin sensitivity.
Conclusions/interpretation
The metabolic benefits of a low-GI diet appear to be more pronounced in younger animals, regardless of the Gipr genotype. Inactivation of GIP signalling in aged animals on a high-GI diet, however, could be beneficial
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