Quantifying differential gene connectivity between disease states for objective identification of disease-relevant genes

<p>Abstract</p> <p>Background</p> <p>Network modeling of whole transcriptome expression data enables characterization of complex epistatic (gene-gene) interactions that underlie cellular functions. Though numerous methods have been proposed and successfully implemented to develop these networks, there are no formal methods for comparing differences in network connectivity patterns as a function of phenotypic trait.</p> <p>Results</p> <p>Here we describe a novel approach for quantifying the differences in gene-gene connectivity patterns across disease states based on Graphical Gaussian Models (GGMs). We compare the posterior probabilities of connectivity for each gene pair across two disease states, expressed as a posterior odds-ratio (postOR) for each pair, which can be used to identify network components most relevant to disease status. The method can also be generalized to model differential gene connectivity patterns within previously defined gene sets, gene networks and pathways. We demonstrate that the GGM method reliably detects differences in network connectivity patterns in datasets of varying sample size. Applying this method to two independent breast cancer expression data sets, we identified numerous reproducible differences in network connectivity across histological grades of breast cancer, including several published gene sets and pathways. Most notably, our model identified two gene hubs (MMP12 and CXCL13) that each exhibited differential connectivity to more than 30 transcripts in both datasets. Both genes have been previously implicated in breast cancer pathobiology, but themselves are not differentially expressed by histologic grade in either dataset, and would thus have not been identified using traditional differential gene expression testing approaches. In addition, 16 curated gene sets demonstrated significant differential connectivity in both data sets, including the matrix metalloproteinases, PPAR alpha sequence targets, and the PUFA synthesis pathway.</p> <p>Conclusions</p> <p>Our results suggest that GGM can be used to formally evaluate differences in global interactome connectivity across disease states, and can serve as a powerful tool for exploring the molecular events that contribute to disease at a systems level.</p

Bacterial defences: mechanisms, evolution and antimicrobial resistance

Throughout their evolutionary history, bacteria have faced diverse threats from other microorganisms, including competing bacteria, bacteriophages and predators. In response to these threats, they have evolved sophisticated defence mechanisms that today also protect bacteria against antibiotics and other therapies. In this Review, we explore the protective strategies of bacteria, including the mechanisms, evolution and clinical implications of these ancient defences. We also review the countermeasures that attackers have evolved to overcome bacterial defences. We argue that understanding how bacteria defend themselves in nature is important for the development of new therapies and for minimizing resistance evolution

A case control study reveals that polyomaviruria is significantly associated with interstitial cystitis and vesical ulceration

Objectives: To investigate whether polyomaviruses contribute to interstitial cystitis pathogenesis. Subjects and Methods: A prospective study was performed with 50 interstitial cystitis cases compared with 50 age-matched, disease-free controls for the frequency of polyomaviruria. Associations between polyomaviruria and disease characteristics were analysed in cases. Polyomavirus in urine and bladder tissue was detected with species (JC virus vs. BK virus) specific, real-time PCR. Results: Case patients were reflective of interstitial cystitis epidemiology with age range from 26–88 years (median 58) and female predominance (41/50 F). There was a significant increase in the frequency of polyomavirus shedding between cases and controls (p<0.02). Polyomavirus shedding, in particular BK viruria, was associated with vesical ulceration, a marker of disease severity, among interstitial cystitis cases after adjustment for age and sex (OR 6.8, 95% CI 1.89–24.4). There was a significant association among cases between the presence of BK viruria and response to intravesical Clorpactin therapy (OR 4.50, 95% CI 1.17–17.4). Conclusion: The presence of polyomaviruria was found to be associated with the ulcerative form of interstitial cystitis. Clorpactin, which has anti-DNA virus activity, was more likely to improve symptoms in the presence of BK viruria. These data from this pilot study suggest associations between polyomaviruria and interstitial cystitis warranting further investigation

Spitzer Secondary Eclipses of the Dense, Modestly-irradiated, Giant Exoplanet HAT-P-20b Using Pixel-Level Decorrelation

HAT-P-20b is a giant exoplanet that orbits a metal-rich star. The planet itself has a high total density, suggesting that it may also have a high metallicity in its atmosphere. We analyze two eclipses of the planet in each of the 3.6- and 4.5 micron bands of Warm Spitzer. These data exhibit intra-pixel detector sensitivity fluctuations that were resistant to traditional decorrelation methods. We have developed a simple, powerful, and radically different method to correct the intra-pixel effect for Warm Spitzer data, which we call pixel-level decorrelation (PLD). PLD corrects the intra-pixel effect very effectively, but without explicitly using - or even measuring - the fluctuations in the apparent position of the stellar image. We illustrate and validate PLD using synthetic and real data, and comparing the results to previous analyses. PLD can significantly reduce or eliminate red noise in Spitzer secondary eclipse photometry, even for eclipses that have proven to be intractable using other methods. Our successful PLD analysis of four HAT-P-20b eclipses shows a best-fit blackbody temperature of 1134 +/-29K, indicating inefficient longitudinal transfer of heat, but lacking evidence for strong molecular absorption. We find sufficient evidence for variability in the 4.5 micron band that the eclipses should be monitored at that wavelength by Spitzer, and this planet should be a high priority for JWST spectroscopy. All four eclipses occur about 35 minutes after orbital phase 0.5, indicating a slightly eccentric orbit. A joint fit of the eclipse and transit times with extant RV data yields e(cos{omega}) = 0.01352 (+0.00054, -0.00057), and establishes the small eccentricity of the orbit to high statistical confidence. Given the existence of a bound stellar companion, HAT-P-20b is another excellent candidate for orbital evolution via Kozai migration or other three-body mechanism.Comment: version published in ApJ, minor text and figure revision

Routine testing for anaerobic bacteria in cerebrospinal fluid cultures improves recovery of clinically significant pathogens

In North America, the widespread use of vaccines targeting Haemophilus influenzae type b and Streptococcus pneumoniae have dramatically altered the epidemiology of bacterial meningitis, while the methodology for culturing cerebrospinal fluid (CSF) specimens has remained largely unchanged. The aims of this study were 2-fold: to document the current epidemiology of bacterial meningitis at a tertiary care medical center and to assess the clinical utility of routinely querying for anaerobes in CSF cultures. To that end, we assessed CSF cultures submitted over a 2-year period. A brucella blood agar (BBA) plate, incubated anaerobically for 5 days, was included in the culture procedure for all CSF specimens during the second year of evaluation. In the pre- and postimplementation years, 2,353 and 2,302 CSF specimens were cultured, with 49 and 99 patients having positive culture results, respectively. The clinical and laboratory data for patients with positive cultures were reviewed. Anaerobic bacteria were isolated in the CSF samples from 33 patients post-BBA compared to two patients pre-BBA (P = 0.01). The anaerobic isolates included Bacteroides thetaiotaomicron (n = 1), Propionibacterium species (n = 15), and Propionibacterium acnes (n = 19) isolates; all of these isolates were recovered on the BBA. Eight of the 35 patients from whom anaerobic organisms were isolated received antimicrobial therapy. Although six of these patients had central nervous system hardware, two patients did not have a history of a neurosurgical procedure and had community-acquired anaerobic bacterial meningitis. This study demonstrates that the simple addition of an anaerobically incubated BBA to the culture of CSF specimens enhances the recovery of clinically significant anaerobic pathogens

Characterisation and stability of anthocyanins in purple-fleshed sweet potato P40

Citation: Xu, J., Su, X., Lim, S., Griffin, J., Carey, E., Katz, B., … Wang, W. (2015). Characterisation and stability of anthocyanins in purple-fleshed sweet potato P40. ISPMF 2015: International Symposium on Phytochemicals in Medicine and Food (Shanghai, China, June 26th –29th, 2015), 186, 90–96. https://doi.org/10.1016/j.foodchem.2014.08.123Purple-fleshed sweet potato P40 has been shown to prevent colorectal cancer in a murine model. This study is to identify anthocyanins by using HPLC/MS–MS and assess the stability during various cooking conditions. P40 possesses a high content of anthocyanins up to 14 mg/g dry matter. Total 12 acylated anthocyanins are identified. Top three anthocyanins, e.g., cyanidin 3-caffeoyl-p-hydroxybenzoyl sophoroside-5-glucoside, peonidin 3-caffeoyl sophoroside-5-glucoside, and cyanidin 3-(6″-caffeoyl-6″-feruloylsophoroside)-5-glucoside, account for half of the anthocyanin contents. Over 80% of anthocyanins measured by acid hydrolysis were cyanidin derivatives, indicating P40 is unique when compared with other purple-fleshed sweet potatoes that usually contain more peonidin than cyanidin. Steaming, pressure cooking, microwaving, and frying but not baking significantly reduced 8–16% of total anthocyanin contents. Mono-acylated anthocyanins showed a higher resistance against heat than di- and non-acylated. Among of which, cyanidin 3-p-hydroxybenzoylsophoroside-5-glucoside exhibited the best thermal stability. The stable acylated and cyanidin-predominated anthocyanins in P40 may provide extra benefits for cancer prevention

The infrared dust bubble N22: an expanding HII region and the star formation around it

Aims. To increase the observational samples of star formation around expanding Hii regions, we analyzed the interstellar medium and star formation around N22. Methods. We used data extracted from the seven large-scale surveys from infrared to radio wavelengths. In addition we used the JCMT observations of the J = 3-2 line of 12CO emission data released on CADC and the 12CO J = 2-1 and J =3-2 lines observed by the KOSMA 3 m telescope. We performed a multiwavelength study of bubble N22. Results. A molecular shell composed of several clumps agrees very well with the border of N22, suggesting that its expansion is collecting the surrounding material. The high integrated 12CO line intensity ratio (ranging from 0.7 to 1.14) implies that shocks have driven into the molecular clouds. We identify eleven possible O-type stars inside the Hii region, five of which are located in projection inside the cavity of the 20 cm radio continuum emission and are probably the exciting-star candidates of N22. Twenty-nine YSOs (young stellar objects) are distributed close to the dense cores of N22. We conclude that star formation is indeed active around N22; the formation of most of YSOs may have been triggered by the expanding of the Hii region. After comparing the dynamical age of N22 and the fragmentation time of the molecular shell, we suggest that radiation-driven compression of pre-existing dense clumps may be ongoing.Comment: accepted in A&A 30/05/2012. arXiv admin note: text overlap with arXiv:1010.5430 by other author

Determining the Parameters of Massive Protostellar Clouds via Radiative Transfer Modeling

A one-dimensional method for reconstructing the structure of prestellar and protostellar clouds is presented. The method is based on radiative transfer computations and a comparison of theoretical and observed intensity distributions at both millimeter and infrared wavelengths. The radiative transfer of dust emission is modeled for specified parameters of the density distribution, central star, and external background, and the theoretical distribution of the dust temperature inside the cloud is determined. The intensity distributions at millimeter and IR wavelengths are computed and quantitatively compared with observational data. The best-fit model parameters are determined using a genetic minimization algorithm, which makes it possible to reveal the ranges of parameter degeneracy as well. The method is illustrated by modeling the structure of the two infrared dark clouds IRDC-320.27+029 (P2) and IRDC-321.73+005 (P2). The derived density and temperature distributions can be used to model the chemical structure and spectral maps in molecular lines.Comment: Accepted for publication in Astronomy Report

Waveguide-integrated and portable optomechanical magnetometer

Optomechanical magnetometers enable highly sensitive magnetic field sensing. However, all such magnetometers to date have been optically excited and read-out either via free space or a tapered optical fiber. This limits their scalability and integrability, and ultimately their range of applications. Here, we present an optomechanical magnetometer that is excited and read out via a suspended optical waveguide fabricated on the same silicon chip as the magnetometer. Moreover, we demonstrate that thermomechanical noise limited sensitivity is possible using portable electronics and laser. The magnetometer employs a silica microdisk resonator selectively sputtered with a magnetostrictive film of galfenol (FeGa) which induces a resonant frequency shift in response to an external magnetic field. Experimental results reveal the retention of high quality-factor optical whispering gallery mode resonances whilst also demonstrating high sensitivity and dynamic range in ambient conditions. The use of off-the-shelf portable electronics without compromising sensor performance demonstrates promise for applications.Comment: 9 pages, 4 figure