Unsupervised Bayesian linear unmixing of gene expression microarrays

Background: This paper introduces a new constrained model and the corresponding algorithm, called unsupervised Bayesian linear unmixing (uBLU), to identify biological signatures from high dimensional assays like gene expression microarrays. The basis for uBLU is a Bayesian model for the data samples which are represented as an additive mixture of random positive gene signatures, called factors, with random positive mixing coefficients, called factor scores, that specify the relative contribution of each signature to a specific sample. The particularity of the proposed method is that uBLU constrains the factor loadings to be non-negative and the factor scores to be probability distributions over the factors. Furthermore, it also provides estimates of the number of factors. A Gibbs sampling strategy is adopted here to generate random samples according to the posterior distribution of the factors, factor scores, and number of factors. These samples are then used to estimate all the unknown parameters. Results: Firstly, the proposed uBLU method is applied to several simulated datasets with known ground truth and compared with previous factor decomposition methods, such as principal component analysis (PCA), non negative matrix factorization (NMF), Bayesian factor regression modeling (BFRM), and the gradient-based algorithm for general matrix factorization (GB-GMF). Secondly, we illustrate the application of uBLU on a real time-evolving gene expression dataset from a recent viral challenge study in which individuals have been inoculated with influenza A/H3N2/Wisconsin. We show that the uBLU method significantly outperforms the other methods on the simulated and real data sets considered here. Conclusions: The results obtained on synthetic and real data illustrate the accuracy of the proposed uBLU method when compared to other factor decomposition methods from the literature (PCA, NMF, BFRM, and GB-GMF). The uBLU method identifies an inflammatory component closely associated with clinical symptom scores collected during the study. Using a constrained model allows recovery of all the inflammatory genes in a single factor

Accuracy and Reproducibility of Voxel Based Superimposition of Cone Beam Computed Tomography Models on the Anterior Cranial Base and the Zygomatic Arches

Superimposition of serial Cone Beam Computed Tomography (CBCT) scans has become a valuable tool for three dimensional (3D) assessment of treatment effects and stability. Voxel based image registration is a newly developed semi-automated technique for superimposition and comparison of two CBCT scans. The accuracy and reproducibility of CBCT superimposition on the anterior cranial base or the zygomatic arches using voxel based image registration was tested in this study. 16 pairs of 3D CBCT models were constructed from pre and post treatment CBCT scans of 16 adult dysgnathic patients. Each pair was registered on the anterior cranial base three times and on the left zygomatic arch twice. Following each superimposition, the mean absolute distances between the 2 models were calculated at 4 regions: anterior cranial base, forehead, left and right zygomatic arches. The mean distances between the models ranged from 0.2 to 0.37 mm (SD 0.08–0.16) for the anterior cranial base registration and from 0.2 to 0.45 mm (SD 0.09–0.27) for the zygomatic arch registration. The mean differences between the two registration zones ranged between 0.12 to 0.19 mm at the 4 regions. Voxel based image registration on both zones could be considered as an accurate and a reproducible method for CBCT superimposition. The left zygomatic arch could be used as a stable structure for the superimposition of smaller field of view CBCT scans where the anterior cranial base is not visible

Short-Term Exposure to Warm Microhabitats Could Explain Amphibian Persistence with Batrachochytrium dendrobatidis

Environmental conditions can alter the outcomes of symbiotic interactions. Many amphibian species have declined due to chytridiomycosis, caused by the pathogenic fungus Batrachochytrium dendrobatidis (Bd), but many others persist despite high Bd infection prevalence. This indicates that Bd's virulence is lower, or it may even be a commensal, in some hosts. In the Australian Wet Tropics, chytridiomycosis extirpated Litoria nannotis from high-elevation rain forests in the early 1990 s. Although the species is recolonizing many sites, no population has fully recovered. Litoria lorica disappeared from all known sites in the early 1990 s and was thought globally extinct, but a new population was discovered in 2008, in an upland dry forest habitat it shares with L. nannotis. All frogs of both species observed during three population censuses were apparently healthy, but most carried Bd. Frogs perch on sun-warmed rocks in dry forest streams, possibly keeping Bd infections below the lethal threshold attained in cooler rain forests. We tested whether short-term elevated temperatures can hamper Bd growth in vitro over one generation (four days). Simulating the temperatures available to frogs on strongly and moderately warmed rocks in dry forests, by incubating cultures at 33°C for one hour daily, reduced Bd growth below that of Bd held at 15°C constantly (representing rain forest habitats). Even small decreases in the exponential growth rate of Bd on hosts may contribute to the survival of frogs in dry forests

Measuring the Meltdown: Drivers of Global Amphibian Extinction and Decline

Habitat loss, climate change, over-exploitation, disease and other factors have been hypothesised in the global decline of amphibian biodiversity. However, the relative importance of and synergies among different drivers are still poorly understood. We present the largest global analysis of roughly 45% of known amphibians (2,583 species) to quantify the influences of life history, climate, human density and habitat loss on declines and extinction risk. Multi-model Bayesian inference reveals that large amphibian species with small geographic range and pronounced seasonality in temperature and precipitation are most likely to be Red-Listed by IUCN. Elevated habitat loss and human densities are also correlated with high threat risk. Range size, habitat loss and more extreme seasonality in precipitation contributed to decline risk in the 2,454 species that declined between 1980 and 2004, compared to species that were stable (n = 1,545) or had increased (n = 28). These empirical results show that amphibian species with restricted ranges should be urgently targeted for conservation

Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment

Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer

Prevalence of HPV infection among Greek women attending a gynecological outpatient clinic

Background: Human papillomavirus (HPV) infection is a causative factor for cervical cancer. Early detection of high risk HPV types might help to identify women at high risk of cervical cancer. The aim of the present study was to examine the HPV prevalence and distribution in cervical smears in a sample of Greek women attending a gynecological outpatient clinic and to explore the determinants of the infection.Methods: A total of 225 women were studied. All women underwent a regular gynecological control. 35 HPV types were studied; 6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 68, 70, 71, 72, 73, 81, 82, 83, 84, 85 and 89. Also, basic demographic information, sociodemographic characteristics and sexual behavior were recorded.Results: HPV was detected in 22.7% of the study population. The percentage of the newly diagnosed women with HPV infection was 17.3%. HPV-16 was the most common type detected (5.3%) followed by HPV-53 (4.9%). 66.2% of the study participants had a Pap test during the last year without any abnormalities. HPV infection was related positively with alcohol consumption (OR: 2.19, 95% CI: 1.04-4.63, P = 0.04) and number of sexual partners (OR: 2.16, 95% CI: 1.44-3.25, P < 0.001), and negatively with age (OR: 0.93, 95% CI: 0.87-0.99, P = 0.03), and monthly income (OR: 0.63, 95% CI: 0.44-0.89, P = 0.01).Conclusion: The prevalence of HPV in women attending an outpatient clinic is high. Number of sexual partners and alcohol consumption were the most significant risk factors for HPV infection, followed by young age and lower income

Functional sex differences in human primary auditory cortex

Background We used PET to study cortical activation during auditory stimulation and found sex differences in the human primary auditory cortex (PAC). Regional cerebral blood flow (rCBF) was measured in 10 male and 10 female volunteers while listening to sounds (music or white noise) and during a baseline (no auditory stimulation). Results and discussion We found a sex difference in activation of the left and right PAC when comparing music to noise. The PAC was more activated by music than by noise in both men and women. But this difference between the two stimuli was significantly higher in men than in women. To investigate whether this difference could be attributed to either music or noise, we compared both stimuli with the baseline and revealed that noise gave a significantly higher activation in the female PAC than in the male PAC. Moreover, the male group showed a deactivation in the right prefrontal cortex when comparing noise to the baseline, which was not present in the female group. Interestingly, the auditory and prefrontal regions are anatomically and functionally linked and the prefrontal cortex is known to be engaged in auditory tasks that involve sustained or selective auditory attention. Thus we hypothesize that differences in attention result in a different deactivation of the right prefrontal cortex, which in turn modulates the activation of the PAC and thus explains the sex differences found in the activation of the PAC. Conclusion Our results suggest that sex is an important factor in auditory brain studies

Hung Out to Dry: Choice of Priority Ecoregions for Conserving Threatened Neotropical Anurans Depends on Life-History Traits

Background: In the Neotropics, nearly 35 % of amphibian species are threatened by habitat loss, habitat fragmentation, and habitat split; anuran species with different developmental modes respond to habitat disturbance in different ways. This entails broad-scale strategies for conserving biodiversity and advocates for the identification of high conservation-value regions that are significant in a global or continental context and that could underpin more detailed conservation assessments towards such areas. Methodology/Principal Findings: We identified key ecoregion sets for anuran conservation using an algorithm that favors complementarity (beta-diversity) among ecoregions. Using the WWF’s Wildfinder database, which encompasses 700 threatened anuran species in 119 Neotropical ecoregions, we separated species into those with aquatic larvae (AL) or terrestrial development (TD), as this life-history trait affects their response to habitat disturbance. The conservation target of 100 % of species representation was attained with a set of 66 ecoregions. Among these, 30 were classified as priority both for species with AL and TD, 26 were priority exclusively for species with AL, and 10 for species with TD only. Priority ecoregions for both developmental modes are concentrated in the Andes and in Mesoamerica. Ecoregions important for conserving species with AL are widely distributed across the Neotropics. When anuran life histories were ignored, species with AL were always underrepresented in priority sets