Identifying aging-related genes in mouse hippocampus using gateway nodes

BACKGROUND: High-throughput studies continue to produce volumes of metadata representing valuable sources of information to better guide biological research. With a stronger focus on data generation, analysis models that can readily identify actual signals have not received the same level of attention. This is due in part to high levels of noise and data heterogeneity, along with a lack of sophisticated algorithms for mining useful information. Networks have emerged as a powerful tool for modeling high-throughput data because they are capable of representing not only individual biological elements but also different types of relationships en masse. Moreover, well-established graph theoretic methodology can be applied to network models to increase efficiency and speed of analysis. In this project, we propose a network model that examines temporal data from mouse hippocampus at the transcriptional level via correlation of gene expression. Using this model, we formally define the concept of “gateway” nodes, loosely defined as nodes representing genes co-expressed in multiple states. We show that the proposed network model allows us to identify target genes implicated in hippocampal aging-related processes. RESULTS: By mining gateway genes related to hippocampal aging from networks made from gene expression in young and middle-aged mice, we provide a proof-of-concept of existence and importance of gateway nodes. Additionally, these results highlight how network analysis can act as a supplement to traditional statistical analysis of differentially expressed genes. Finally, we use the gateway nodes identified by our method as well as functional databases and literature to propose new targets for study of aging in the mouse hippocampus. CONCLUSIONS: This research highlights the need for methods of temporal comparison using network models and provides a systems biology approach to extract information from correlation networks of gene expression. Our results identify a number of genes previously implicated in the aging mouse hippocampus related to synaptic plasticity and apoptosis. Additionally, this model identifies a novel set of aging genes previously uncharacterized in the hippocampus. This research can be viewed as a first-step for identifying the processes behind comparative experiments in aging that is applicable to any type of temporal multi-state network

Roles for transforming growth factor-alpha in gastric physiology and pathophysiology.

Transforming growth factor alpha (TGF alpha) is a 5.6 kd single-chain polypeptide that acts through binding to the epidermal growth factor receptor (EGFR). TGF alpha is produced in a wide range of normal as well as embryonic and neoplastic cells and tissues. TGF alpha and EGFR, but not EGF, are expressed in normal gastric mucosa. We have identified the following biological roles for TGF alpha in the stomach, using a variety of primate and rodent models: inhibition of acid secretion; stimulation of mucous cell growth; protection against ethanol- and aspirin-induced injury. This last effect is associated with a time- and dose-dependent increase in levels of insoluble gastric mucin. Based on these known biological actions of TGF alpha, we have examined TGF alpha production in Ménétrier's disease, a disorder characterized by foveolar hyperplasia, hypochlorhydria, and increased gastric mucin content. In four patients with Ménétrier's disease, there was enhanced TGF alpha immunostaining throughout the gastric mucosa. Furthermore, metallothionein (MT)-TGF alpha transgenic mice which overproduce TGF alpha in the stomach exhibit histopathological and biochemical features characteristic of and consistent with the diagnosis of Ménétrier's disease. Thus locally produced TGF alpha may mediate a number of biological processes in the stomach, and its altered production may participate in the pathogenesis of selected pathological states

Memorization of short-range potential fluctuations in Landau levels

We calculate energy spectra of a two-dimensional electron system in a perpendicular magnetic field and periodic potentials of short periods. The Coulomb interaction is included within a screened Hartree-Fock approximation. The electrostatic screening is poor and the exchange interaction amplifies the energy dispersion. We obtain, by numerical iterations, self-consistent solutions that have a hysteresis-like property. With increasing amplitude of the external potential the energy dispersion and the electron density become periodic, and they remain stable when the external potential is reduced to zero. We explain this property in physical terms and speculate that a real system could memorize short-range potential fluctuations after the potential has been turned off.Comment: 11 pages with 4 included figures, Revte

CHIMPS: the ¹³CO/C¹⁸O (<i>J</i> = 3 → 2) Heterodyne Inner Milky Way Plane Survey

We present the 13CO/C18O (J = 3 → 2) Heterodyne Inner Milky Way Plane Survey (CHIMPS) which has been carried out using the Heterodyne Array Receiver Program on the 15 m James Clerk Maxwell Telescope (JCMT) in Hawaii. The high-resolution spectral survey currently covers |b| ≤ 0.5° and 28° ≲ l ≲ 46°, with an angular resolution of 15 arcsec in 0.5 km s-1 velocity channels. The spectra have a median rms of ˜0.6 K at this resolution, and for optically thin gas at an excitation temperature of 10 K, this sensitivity corresponds to column densities of NH2 ˜ 3 × 1020 cm-2 and NH2 ˜ 4 × 1021 cm-2 for 13CO and C18O, respectively. The molecular gas that CHIMPS traces is at higher column densities and is also more optically thin than in other publicly available CO surveys due to its rarer isotopologues, and thus more representative of the three-dimensional structure of the clouds. The critical density of the J = 3 → 2 transition of CO is ≳104 cm-3 at temperatures of ≤20 K, and so the higher density gas associated with star formation is well traced. These data complement other existing Galactic plane surveys, especially the JCMT Galactic Plane Survey which has similar spatial resolution and column density sensitivity, and the Herschel infrared Galactic Plane Survey. In this paper, we discuss the observations, data reduction and characteristics of the survey, presenting integrated-emission maps for the region covered. Position-velocity diagrams allow comparison with Galactic structure models of the Milky Way, and while we find good agreement with a particular four-arm model, there are some significant deviations

A Search for Propylene Oxide and Glycine in Sagittarius B2 (LMH) and Orion

We have used the Mopra Telescope to search for glycine and the simple chiral molecule propylene oxide in the Sgr B2 (LMH) and Orion KL, in the 3-mm band. We have not detected either species, but have been able to put sensitive upper limits on the abundances of both molecules. The 3-sigma upper limits derived for glycine conformer I are 3.7 x 10^{14} cm^{-2} in both Orion-KL and Sgr B2 (LMH), comparable to the reported detections of conformer I by Kuan et al. However, as our values are 3-sigma upper limits rather than detections we conclude that this weighs against confirming the detection of Kuan et al. We find upper limits for the glycine II column density of 7.7 x 10^{12} cm^{-2} in both Orion-KL and Sgr B2 (LMH), in agreement with the results of Combes et al. The results presented here show that glycine conformer II is not present in the extended gas at the levels detected by Kuan et al. for conformer I. Our ATCA results (Jones et al.) have ruled out the detection of glycine (both conformers I and II) in the compact hot core of the LMH at the levels reported, so we conclude that it is unlikely that Kuan et al. have detected glycine in either Sgr B2 or Orion-KL. We find upper limits for propylene oxide abundance of 3.0 x 10^{14} cm^{-2} in Orion-KL and 6.7 x 10^{14} cm^{-2} in Sgr B2 (LMH). We have detected fourteen features in Sgr B2 and four features in Orion-KL which have not previously been reported in the ISM, but have not be able to plausibly assign these transitions to any carrier.Comment: 12 pages, 3 figures. Accepted by MNRAS 12th January 200

Blood-based biomarkers for detecting mild osteoarthritis in the human knee

SummaryObjectiveThis study was designed to test the utility of a blood-based approach to identify mild osteoarthritis (OA) of the knee.MethodsBlood samples were drawn from 161 subjects, including 85 subjects with arthroscopically diagnosed mild OA of the knee and 76 controls. Following RNA isolation, an in-house custom cDNA microarray was used to screen for differentially expressed genes. A subset of selected genes was then tested using real-time RT-PCR. Logistic regression analysis was used to evaluate linear combinations of the biomarkers and receiver operating characteristic curve analysis was used to assess the discriminatory power of the combinations.ResultsGenes differentially expressed (3543 genes) between mild knee OA and control samples were identified through microarray analysis. Subsequent real-time RT-PCR verification identified six genes significantly down-regulated in mild OA: heat shock 90kDa protein 1, alpha; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein; interleukin 13 receptor, alpha 1; laminin, gamma 1; platelet factor 4 (also known as chemokine (C-X-C motif) ligand 4) and tumor necrosis factor, alpha-induced protein 6. Logistic regression analysis identified linear combinations of nine genes – the above six genes, early growth response 1; alpha glucosidase II alpha subunit; and v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (avian) – as discriminatory between subjects with mild OA and controls, with a sensitivity of 86% and specificity of 83% in a training set of 78 samples. The optimal biomarker combinations were then evaluated using a blind test set (67 subjects) which showed 72% sensitivity and 66% specificity.ConclusionsLinear combinations of blood RNA biomarkers offer a substantial improvement over currently available diagnostic tools for mild OA. Blood-derived RNA biomarkers may be of significant clinical value for the diagnosis of early, asymptomatic OA of the knee

Fabrication of magnetocaloric La(Fe,Si)13_{13} thick films

La(Fe,Si)$_{13}$-based compounds are considered to be very promising magnetocaloric materials for magnetic refrigeration applications. Many studies have focused on this material family but only in bulk form. In this paper, we report the fabrication of thick films of La(Fe,Si)$_{13}$, both with and without post-hydriding. These films exhibit magnetic and structural properties comparable to those of bulk materials. We also observe that the ferromagnetic phase transition has a negative thermal hysteresis, a phenomenon not previously found in this material but which may have its origins in the availability of a strain energy reservoir, as in the cases of other materials in which negative thermal hysteresis has been found. Here, it appears that the substrate acts to store strain energy. Our exploratory study demonstrates the viability of thick films of the La(Fe,Si)$_{13}$ phase and motivates further work in the area, while showing that additional perspectives can be gained from reducing the dimensionality of magnetocaloric materials in which the magneto-volume effect is large.Comment: 16 pages, 3 figure

Statistical evolution of isotope composition of nuclear fragments

Calculations within the statistical multifragmentation model show that the neutron content of intermediate mass fragments can increase in the region of liquid-gas phase transition in finite nuclei. The model predicts also inhomogeneous distributions of fragments and their isospin in the freeze-out volume caused by an angular momentum and external long-range Coulomb field. These effects can take place in peripheral nucleus-nucleus collisions at intermediate energies and lead to neutron-rich isotopes produced in the midrapidity kinematic region.Comment: 14 pages with 4 figures. GSI preprint, Darmstadt, 200

Human perceptual learning is delayed by the N-methyl-D-aspartate receptor partial agonist D-cycloserine

Background: The optimisation of learning has long been a focus of scientific research, particularly in relation to improving psychological treatment and recovery of brain function. Previously, partial N-methyl-D-aspartate agonists have been shown to augment reward learning, procedural learning and psychological therapy, but many studies also report no impact of these compounds on the same processes. Aims: Here we investigate whether administration of an N-methyl-D-aspartate partial agonist (D-cycloserine) modulates a previously unexplored process – tactile perceptual learning. Further, we use a longitudinal design to investigate whether N-methyl-D-aspartate-related learning effects vary with time, thereby providing a potentially simple explanation for apparent mixed effects in previous research. Methods: Thirty-four volunteers were randomised to receive one dose of 250 mg D-cycloserine or placebo 2 h before tactile sensitivity training. Tactile perception was measured using psychophysical methods before and after training, and 24/48 h later. Results: The placebo group showed immediate within-day tactile perception gains, but no further improvements between-days. In contrast, tactile perception remained at baseline on day one in the D-cycloserine group (no within-day learning), but showed significant overnight gains on day two. Both groups were equivalent in tactile perception by the final testing – indicating N-methyl-D-aspartate effects changed the timing, but not the overall amount of tactile learning. Conclusions: In sum, we provide first evidence for modulation of perceptual learning by administration of a partial N-methyl-D-aspartate agonist. Resolving how the effects of such compounds become apparent over time will assist the optimisation of testing schedules, and may help resolve discrepancies across the learning and cognition domains