An Empirical Comparison of Information-Theoretic Criteria in Estimating the Number of Independent Components of fMRI Data

BACKGROUND: Independent Component Analysis (ICA) has been widely applied to the analysis of fMRI data. Accurate estimation of the number of independent components of fMRI data is critical to reduce over/under fitting. Although various methods based on Information Theoretic Criteria (ITC) have been used to estimate the intrinsic dimension of fMRI data, the relative performance of different ITC in the context of the ICA model hasn't been fully investigated, especially considering the properties of fMRI data. The present study explores and evaluates the performance of various ITC for the fMRI data with varied white noise levels, colored noise levels, temporal data sizes and spatial smoothness degrees. METHODOLOGY: Both simulated data and real fMRI data with varied Gaussian white noise levels, first-order auto-regressive (AR(1)) noise levels, temporal data sizes and spatial smoothness degrees were carried out to deeply explore and evaluate the performance of different traditional ITC. PRINCIPAL FINDINGS: Results indicate that the performance of ITCs depends on the noise level, temporal data size and spatial smoothness of fMRI data. 1) High white noise levels may lead to underestimation of all criteria and MDL/BIC has the severest underestimation at the higher Gaussian white noise level. 2) Colored noise may result in overestimation that can be intensified by the increase of AR(1) coefficient rather than the SD of AR(1) noise and MDL/BIC shows the least overestimation. 3) Larger temporal data size will be better for estimation for the model of white noise but tends to cause severer overestimation for the model of AR(1) noise. 4) Spatial smoothing will result in overestimation in both noise models. CONCLUSIONS: 1) None of ITC is perfect for all fMRI data due to its complicated noise structure. 2) If there is only white noise in data, AIC is preferred when the noise level is high and otherwise, Laplace approximation is a better choice. 3) When colored noise exists in data, MDL/BIC outperforms the other criteria

Do Larval Supply and Recruitment Vary among Chemosynthetic Environments of the Deep Sea?

BACKGROUND: The biological communities that inhabit chemosynthetic environments exist in an ephemeral and patchily distributed habitat with unique physicochemical properties that lead to high endemicity. Consequently, the maintenance and recovery from perturbation of the populations in these habitats is, arguably, mainly regulated by larval supply and recruitment. METHODOLOGY/PRINCIPAL FINDINGS: WE USE DATA FROM THE PUBLISHED SCIENTIFIC LITERATURE TO: (1) compare the magnitudes of and variability in larval supply and settlement and recruitment at hydrothermal vents, seeps, and whale, wood and kelp falls; (2) explore factors that affect these life history processes, when information is available; and (3) explore taxonomic affinities in the recruit assemblages of the different chemosynthetic habitats, using multivariate statistical techniques. Larval supply at vents can vary across segments by several orders of magnitude for gastropods; for bivalves, supply is similar at vents on different segments, and at cold seeps. The limited information on larval development suggests that dispersal potential may be highest for molluscs from cold seeps, intermediate for siboglinids at vents and lowest for the whale-bone siboglinid Osedax. Settlement is poorly studied and only at vents and seeps, but tends to be highest near an active source of emanating fluid in both habitats. Rate of recruitment at vents is more variable among studies within a segment than among segments. Across different chemosynthetic habitats, recruitment rate of bivalves is much more variable than that of gastropods and polychaetes. Total recruitment rate ranges only between 0.1 and 1 ind dm(-2) d(-1) across all chemosynthetic habitats, falling above rates in the non-reducing deep sea. The recruit assemblages at vents, seeps and kelp falls have lower taxonomic breadth, and include more families and genera that have many species more closely related to each other than those at whale and wood falls. Vents also have the most uneven taxonomic structure, with fewer recruits represented by higher taxonomic levels (phyla, orders, classes) compared to seeps and wood and kelp falls, whereas the opposite is true at whale falls. CONCLUSIONS/SIGNIFICANCE: Based on our evaluation of the literature, the patterns and regulatory factors of the early history processes in chemosynthetic environments in the deep sea remain poorly understood. More research focused on these early life history stages will allow us to make inferences about the ecological and biogeographic linkages among the reducing habitats in the deep sea

β1 Integrin-Mediated Adhesion Signalling Is Essential for Epidermal Progenitor Cell Expansion

Background: There is a major discrepancy between the in vitro and in vivo results regarding the role of b1 integrins in the maintenance of epidermal stem/progenitor cells. Studies of mice with skin-specific ablation of b1 integrins suggested that epidermis can form and be maintained in their absence, while in vitro data have shown a fundamental role for these adhesion receptors in stem/progenitor cell expansion and differentiation. Methodology/Principal Findings: To elucidate this discrepancy we generated hypomorphic mice expressing reduced b1 integrin levels on keratinocytes that developed similar, but less severe defects than mice with b1-deficient keratinocytes. Surprisingly we found that upon aging these abnormalities attenuated due to a rapid expansion of cells, which escaped or compensated for the down-regulation of b1 integrin expression. A similar phenomenon was observed in aged mice with a complete, skin-specific ablation of the b1 integrin gene, where cells that escaped Cre-mediated recombination repopulated the mutant skin in a very short time period. The expansion of b1 integrin expressing keratinocytes was even further accelerated in situations of increased keratinocyte proliferation such as wound healing. Conclusions/Significance: These data demonstrate that expression of b1 integrins is critically important for the expansion of epidermal progenitor cells to maintain epidermal homeostasis

Long Distance Movements and Disjunct Spatial Use of Harbor Seals (Phoca vitulina) in the Inland Waters of the Pacific Northwest

BACKGROUND: Worldwide, adult harbor seals (Phoca vitulina) typically limit their movements and activity to <50 km from their primary haul-out site. As a result, the ecological impact of harbor seals is viewed as limited to relatively small spatial scales. Harbor seals in the Pacific Northwest are believed to remain <30 km from their primary haul-out site, one of several contributing factors to the current stock designation. However, movement patterns within the region are not well understood because previous studies have used radio-telemetry, which has range limitations. Our objective was to use satellite-telemetry to determine the regional spatial scale of movements. METHODOLOGY/PRINCIPAL FINDINGS: Satellite tags were deployed on 20 adult seals (n=16 males and 4 females) from two rocky reefs and a mudflat-bay during April-May 2007. Standard filtering algorithms were used to remove outliers, resulting in an average (± SD) of 693 (± 377) locations per seal over 110 (± 32) days. A particle filter was implemented to interpolate locations temporally and decrease erroneous locations on land. Minimum over-water distances were calculated between filtered locations and each seal's capture site to show movement of seals over time relative to their capture site, and we estimated utilization distributions from kernel density analysis to reflect spatial use. Eight males moved >100 km from their capture site at least once, two of which traveled round trip to and from the Pacific coast, a total distance >400 km. Disjunct spatial use patterns observed provide new insight into general harbor seal behavior. CONCLUSIONS/SIGNIFICANCE: Long-distance movements and disjunct spatial use of adult harbor seals have not been reported for the study region and are rare worldwide in such a large proportion of tagged individuals. Thus, the ecological influence of individual seals may reach farther than previously assumed

Drug-Selected Human Lung Cancer Stem Cells: Cytokine Network, Tumorigenic and Metastatic Properties

Background: Cancer stem cells (CSCs) are thought to be responsible for tumor regeneration after chemotherapy, although direct confirmation of this remains forthcoming. We therefore investigated whether drug treatment could enrich and maintain CSCs and whether the high tumorogenic and metastatic abilities of CSCs were based on their marked ability to produce growth and angiogenic factors and express their cognate receptors to stimulate tumor cell proliferation and stroma formation. Methodology/Findings: Treatment of lung tumor cells with doxorubicin, cisplatin, or etoposide resulted in the selection of drug surviving cells (DSCs). These cells expressed CD133, CD117, SSEA-3, TRA1-81, Oct-4, and nuclear β-catenin and lost expression of the differentiation markers cytokeratins 8/18 (CK 8/18). DSCs were able to grow as tumor spheres, maintain self-renewal capacity, and differentiate. Differentiated progenitors lost expression of CD133, gained CK 8/18 and acquired drug sensitivity. In the presence of drugs, differentiation of DSCs was abrogated allowing propagation of cells with CSC-like characteristics. Lung DSCs demonstrated high tumorogenic and metastatic potential following inoculation into SCID mice, which supported their classification as CSCs. Luminex analysis of human and murine cytokines in sonicated lysates of parental- and CSC-derived tumors revealed that CSC-derived tumors contained two- to three-fold higher levels of human angiogenic and growth factors (VEGF, bFGF, IL-6, IL-8, HGF, PDGF-BB, G-CSF, and SCGF-β). CSCs also showed elevated levels of expression of human VEGFR2, FGFR2, CXCR1, 2 and 4 receptors. Moreover, human CSCs growing in SCID mice stimulated murine stroma to produce elevated levels of angiogenic and growth factors. Conlusions/Significance: These findings suggest that chemotherapy can lead to propagation of CSCs and prevention of their differentiation. The high tumorigenic and metastatic potentials of CSCs are associated with efficient cytokine network production that may represent a target for increased efficacy of cancer therapy. © 2008 Levina et al

Precision and accuracy of single-molecule FRET measurements - a multi-laboratory benchmark study

Single-molecule Förster resonance energy transfer (smFRET) is increasingly being used to determine distances, structures, and dynamics of biomolecules in vitro and in vivo. However, generalized protocols and FRET standards to ensure the reproducibility and accuracy of measurements of FRET efficiencies are currently lacking. Here we report the results of a comparative blind study in which 20 labs determined the FRET efficiencies (E) of several dye-labeled DNA duplexes. Using a unified, straightforward method, we obtained FRET efficiencies with s.d. between ±0.02 and ±0.05. We suggest experimental and computational procedures for converting FRET efficiencies into accurate distances, and discuss potential uncertainties in the experiment and the modeling. Our quantitative assessment of the reproducibility of intensity-based smFRET measurements and a unified correction procedure represents an important step toward the validation of distance networks, with the ultimate aim of achieving reliable structural models of biomolecular systems by smFRET-based hybrid methods

Quantifying Sources of Variability in Infancy Research Using the Infant-Directed-Speech Preference

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era