Extreme between-study homogeneity in meta-analyses could offer useful insights.

PubMed

Ioannidis, John P A; Trikalinos, Thomas A; Zintzaras, Elias

2006-10-01

Meta-analyses are routinely evaluated for the presence of large between-study heterogeneity. We examined whether it is also important to probe whether there is extreme between-study homogeneity. We used heterogeneity tests with left-sided statistical significance for inference and developed a Monte Carlo simulation test for testing extreme homogeneity in risk ratios across studies, using the empiric distribution of the summary risk ratio and heterogeneity statistic. A left-sided P=0.01 threshold was set for claiming extreme homogeneity to minimize type I error. Among 11,803 meta-analyses with binary contrasts from the Cochrane Library, 143 (1.21%) had left-sided P-value <0.01 for the asymptotic Q statistic and 1,004 (8.50%) had left-sided P-value <0.10. The frequency of extreme between-study homogeneity did not depend on the number of studies in the meta-analyses. We identified examples where extreme between-study homogeneity (left-sided P-value <0.01) could result from various possibilities beyond chance. These included inappropriate statistical inference (asymptotic vs. Monte Carlo), use of a specific effect metric, correlated data or stratification using strong predictors of outcome, and biases and potential fraud. Extreme between-study homogeneity may provide useful insights about a meta-analysis and its constituent studies.

Query-Based Outlier Detection in Heterogeneous Information Networks.

PubMed

Kuck, Jonathan; Zhuang, Honglei; Yan, Xifeng; Cam, Hasan; Han, Jiawei

2015-03-01

Outlier or anomaly detection in large data sets is a fundamental task in data science, with broad applications. However, in real data sets with high-dimensional space, most outliers are hidden in certain dimensional combinations and are relative to a user's search space and interest. It is often more effective to give power to users and allow them to specify outlier queries flexibly, and the system will then process such mining queries efficiently. In this study, we introduce the concept of query-based outlier in heterogeneous information networks, design a query language to facilitate users to specify such queries flexibly, define a good outlier measure in heterogeneous networks, and study how to process outlier queries efficiently in large data sets. Our experiments on real data sets show that following such a methodology, interesting outliers can be defined and uncovered flexibly and effectively in large heterogeneous networks.

Query-Based Outlier Detection in Heterogeneous Information Networks

PubMed Central

Kuck, Jonathan; Zhuang, Honglei; Yan, Xifeng; Cam, Hasan; Han, Jiawei

2015-01-01

Outlier or anomaly detection in large data sets is a fundamental task in data science, with broad applications. However, in real data sets with high-dimensional space, most outliers are hidden in certain dimensional combinations and are relative to a user’s search space and interest. It is often more effective to give power to users and allow them to specify outlier queries flexibly, and the system will then process such mining queries efficiently. In this study, we introduce the concept of query-based outlier in heterogeneous information networks, design a query language to facilitate users to specify such queries flexibly, define a good outlier measure in heterogeneous networks, and study how to process outlier queries efficiently in large data sets. Our experiments on real data sets show that following such a methodology, interesting outliers can be defined and uncovered flexibly and effectively in large heterogeneous networks. PMID:27064397

Response Styles in Rating Scales: Simultaneous Modeling of Content-Related Effects and the Tendency to Middle or Extreme Categories

ERIC Educational Resources Information Center

Tutz, Gerhard; Berger, Moritz

2016-01-01

Heterogeneity in response styles can affect the conclusions drawn from rating scale data. In particular, biased estimates can be expected if one ignores a tendency to middle categories or to extreme categories. An adjacent categories model is proposed that simultaneously models the content-related effects and the heterogeneity in response styles.…

"Super-quenching" state protects Symbiodinium from thermal stress - Implications for coral bleaching.

PubMed

Slavov, Chavdar; Schrameyer, Verena; Reus, Michael; Ralph, Peter J; Hill, Ross; Büchel, Claudia; Larkum, Anthony W D; Holzwarth, Alfred R

2016-06-01

The global rise in sea surface temperatures causes regular exposure of corals to high temperature and high light stress, leading to worldwide disastrous coral bleaching events (loss of symbiotic dinoflagellates (Symbiodinium) from reef-building corals). Our picosecond chlorophyll fluorescence experiments on cultured Symbiodinium clade C cells exposed to coral bleaching conditions uncovered the transformations of the alga's photosynthetic apparatus (PSA) that activate an extremely efficient non-photochemical "super-quenching" mechanism. The mechanism is associated with a transition from an initially heterogeneous photosystem II (PSII) pool to a homogeneous "spillover" pool, where nearly all excitation energy is transferred to photosystem I (PSI). There, the inherently higher stability of PSI and high quenching efficiency of P(700)(+) allow dumping of PSII excess excitation energy into heat, resulting in almost complete cessation of photosynthetic electron transport (PET). This potentially reversible "super-quenching" mechanism protects the PSA against destruction at the cost of a loss of photosynthetic activity. We suggest that the inhibition of PET and the consequent inhibition of organic carbon production (e.g. sugars) in the symbiotic Symbiodinium provide a trigger for the symbiont expulsion, i.e. bleaching. Copyright © 2016. Published by Elsevier B.V.

Heterogeneity in brain reactivity to pleasant and food cues: evidence of sign-tracking in humans

PubMed Central

Versace, Francesco; Kypriotakis, George; Basen-Engquist, Karen

2016-01-01

Aberrant brain reward responses to food-related cues are an implied characteristic of human obesity; yet, findings are inconsistent. To explain these inconsistencies, we aimed to uncover endophenotypes associated with heterogeneity in attributing incentive salience to food cues in the context of other emotionally salient cues; a phenomenon described as sign- vs goal tracking in preclinical models. Data from 64 lean and 88 obese adults who were 35.5 ± 9.4 years old and predominantly women (79%) were analyzed. Participants viewed food-related, pleasant, neutral and unpleasant images while recording electroencephalograph. Late positive potentials were used to assess incentive salience attributed to the visual stimuli. Eating and affective traits were also assessed. Findings demonstrated that obese individuals, in general, do not demonstrate aberrant brain reward responses to food-related cues. As hypothesized, latent profile analysis of the late positive potential uncovered two distinct groups. ‘Sign-trackers’ showed greater responses to food-related cues (P < 0.001) but lower responses to pleasant stimuli (P < 0.001) compared with ‘goal-trackers’. There were proportionally more obese than lean ‘sign-trackers’ (P = 0.03). Obese ‘sign-trackers’ reported significantly higher levels of emotional eating and food craving (P < 0.001). By examining the heterogeneity in brain reactivity to various emotional stimuli, this translational study highlights the need to consider important neurobehavioral endophenotypes of obesity. PMID:26609106

Uncovering stem-cell heterogeneity in the microniche with label-free microfluidics

NASA Astrophysics Data System (ADS)

Sohn, Lydia L.

2013-03-01

Better suited for large number of cells from bulk tissue, traditional cell-screening techniques, such as fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS), cannot easily screen stem or progenitor cells from minute populations found in their physiological niches. Furthermore, they rely upon irreversible antibody binding, potentially altering cell properties, including gene expression and regenerative capacity. We have developed a label-free, single-cell analysis microfluidic platform capable of quantifying cell-surface marker expression of functional organ stem cells directly isolated from their micro-anatomical niche. With this platform, we have screened single quiescent muscle stem (satellite) cells derived from single myofibers, and we have uncovered an important heterogeneity in the surface-marker expression of these cells. By sorting the screened cells with our microfluidic device, we have determined what this heterogeneity means in terms of muscle stem-cell functionality. For instance, we show that the levels of beta1-integrin can predict the differentiation capacity of quiescent satellite cells, and in contrast to recent literature, that some CXCR4 + cells are not myogenic. Our results provide the first direct demonstration of a microniche-specific variation in gene expression in stem cells of the same lineage. Overall, our label-free, single-cell analysis and cell-sorting platform could be extended to other systems involving rare-cell subsets. This work was funded by the W. M. Keck Foundation, NIH, and California Institute of Regenerative Medicine

Labeling Actors and Uncovering Causal Accounts of Their States in Social Networks and Social Media

ERIC Educational Resources Information Center

Bui, Ngot P.

2016-01-01

The emergence of social networks and social media has resulted in exponential increase in the amount of data that link diverse types of richly structured digital objects e.g., individuals, articles, images, videos, music, etc. Such data are naturally represented as heterogeneous networks with multiple types of objects e.g., actors, video,…

A weighted U statistic for association analyses considering genetic heterogeneity.

PubMed

Wei, Changshuai; Elston, Robert C; Lu, Qing

2016-07-20

Converging evidence suggests that common complex diseases with the same or similar clinical manifestations could have different underlying genetic etiologies. While current research interests have shifted toward uncovering rare variants and structural variations predisposing to human diseases, the impact of heterogeneity in genetic studies of complex diseases has been largely overlooked. Most of the existing statistical methods assume the disease under investigation has a homogeneous genetic effect and could, therefore, have low power if the disease undergoes heterogeneous pathophysiological and etiological processes. In this paper, we propose a heterogeneity-weighted U (HWU) method for association analyses considering genetic heterogeneity. HWU can be applied to various types of phenotypes (e.g., binary and continuous) and is computationally efficient for high-dimensional genetic data. Through simulations, we showed the advantage of HWU when the underlying genetic etiology of a disease was heterogeneous, as well as the robustness of HWU against different model assumptions (e.g., phenotype distributions). Using HWU, we conducted a genome-wide analysis of nicotine dependence from the Study of Addiction: Genetics and Environments dataset. The genome-wide analysis of nearly one million genetic markers took 7h, identifying heterogeneous effects of two new genes (i.e., CYP3A5 and IKBKB) on nicotine dependence. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Selectively bred rat model system for low and high response to exercise training

PubMed Central

Pollott, Geoffrey E.; Britton, Steven L.

2013-01-01

We initiated a large-scale bidirectional selection experiment in a genetically heterogeneous rat population (N/NIH stock, n = 152) to develop lines of low response trainers (LRT) and high response trainers (HRT) as a contrasting animal model system. Maximal treadmill running distance [meters (m)] was tested before (DIST1) and after (DIST2) standardized aerobic treadmill training over an 8 wk period (3 exercise sessions per week). Response to training was calculated as the change in exercise capacity (ΔDIST = DIST2 − DIST1). A within-family selection and rotational breeding paradigm between 10 families was practiced for both selected lines. For the founder population, exercise training produced a 140 ± 15 m gain in exercise capacity with interindividual variation ranging from −339 to +627 m. After 15 generations of selection (n = 3,114 rats), HRT rats improved 223 ± 20 m as a result of exercise training while exercise capacity declined −65 ± 15 m in LRT rats given the same absolute training environment. The narrow-sense heritability (h2) for ΔDIST was 0.10 ± 0.02. The LRT and HRT lines did not differ significantly for body weight or intrinsic (i.e., DIST1) exercise capacity. Using pedigree records the inbreeding coefficient increased at a rate of 1.7% per generation for HRT and 1.6% per generation for LRT, ∼30% slower than expected from random mating. Animal models developed from heterogeneous stock and enriched via selection, as presented here, often generate extreme values for traits of interest and may prove more useful than current models for uncovering genetic underpinnings. PMID:23715262

Visual analysis of large heterogeneous social networks by semantic and structural abstraction.

PubMed

Shen, Zeqian; Ma, Kwan-Liu; Eliassi-Rad, Tina

2006-01-01

Social network analysis is an active area of study beyond sociology. It uncovers the invisible relationships between actors in a network and provides understanding of social processes and behaviors. It has become an important technique in a variety of application areas such as the Web, organizational studies, and homeland security. This paper presents a visual analytics tool, OntoVis, for understanding large, heterogeneous social networks, in which nodes and links could represent different concepts and relations, respectively. These concepts and relations are related through an ontology (also known as a schema). OntoVis is named such because it uses information in the ontology associated with a social network to semantically prune a large, heterogeneous network. In addition to semantic abstraction, OntoVis also allows users to do structural abstraction and importance filtering to make large networks manageable and to facilitate analytic reasoning. All these unique capabilities of OntoVis are illustrated with several case studies.

Root and shoot transcriptome analysis of two ecotypes of Noccaea caerulescens uncovers the role of NcNramp1 in Cd hyperaccumulation

USDA-ARS?s Scientific Manuscript database

The Zn/Cd hyperaccumulator, Noccaea caerulescens, has been studied extensively for its ability to accumulate Zn and Cd in its leaves to extremely high levels. Previous studies have indicated that the Zn and Cd hyperaccumulation trait exhibited by this species involves different transport and toleran...

Applying Physics Concepts--Uncovering the Gender Differences in Assessment of Performance Unit Results.

ERIC Educational Resources Information Center

Bransky, Judith; Qualter, Anne

1993-01-01

Describes the findings of secondary analysis of data from the Assessment of Performance Unit (APU) Science. The most striking feature of the study is the extremely low level of scores obtained for questions which invite a written response. The results also clearly show the consistent negative reaction of girls to the technical context of…

The Foreign-Language Teacher and Cognitive Psychology or Where Do We Go from Here?

ERIC Educational Resources Information Center

Rivers, Wilga M.

Research into the psychology of perception can uncover important discoveries for more efficient learning. There must be increased understanding of the processing of input and the pre-processing of output for improved language instruction. Educators must at the present time be extremely wary of basing what they do in the foreign-language classroom…

Pluridirectional High-Energy Agile Scanning Electron Radiotherapy (PHASER): Extremely Rapid Treatment for Early Lung Cancer

DTIC Science & Technology

2015-09-01

used to simulate 50- 150MeV VHEE beam dose deposition and its effects on steel and titanium (Ti) heterogeneities in a water phantom. Heterogeneities of...and water with segmented prostheses ( steel and Ti) geometries with 100MeV and 150MeV beams. Results: 100MeV PDD 5cm behind steel /Ti heterogeneity...in steel and 18% in Ti heterogeneities. The dose immediately behind steel heterogeneity decreased by an average of 6%, although for 150MeV, the

Dynamical structure of extreme ultraviolet macrospicules

NASA Technical Reports Server (NTRS)

Karovska, Margarita; Habbal, Shadia Rifai

1994-01-01

We describe the substructures forming the macrospicules and their temporal evolution, as revealed by the application of an image enhancement algorithm to extreme ultraviolet (EUV) observations of macrospicules. The enhanced images uncover, for the first time, the substructures forming the column-like structures within the macrospicules and the low-lying arches at their base. The spatial and temporal evolution of macrospicules clearly show continuous interaction between these substructures with occasional ejection of plasma following a ballistic trajectory. We comment on the importance of these results for planning near future space observations of macrospicules with better temporal and spatial resolution.

A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60

PubMed Central

Ben Said, Mariem; Grati, M’hamed; Ishimoto, Takahiro; Zou, Bing; Chakchouk, Imen; Ma, Qi; Yao, Qi; Hammami, Bouthaina; Yan, Denise; Mittal, Rahul; Nakamichi, Noritaka; Ghorbel, Abdelmonem; Neng, Lingling; Tekin, Mustafa; Shi, Xiao Rui; Kato, Yukio; Masmoudi, Saber; Lu, Zhongmin; Hmani, Mounira; Liu, Xuezhong

2016-01-01

The high prevalence/incidence of hearing loss (HL) in humans makes it the most common sensory defect. The majority of the cases are of genetic origin. Non-syndromic hereditary HL is extremely heterogeneous. Genetic approaches have been instrumental in deciphering genes that are crucial for auditory function. In this study, we first used NADf chip to exclude the implication of known North-African mutations in HL in a large consanguineous Tunisian family (FT13) affected by autosomal recessive non-syndromic HL (ARNSHL). We then performed genome-wide linkage analysis and assigned the deafness gene locus to ch:5q23.2-31.1, corresponding to DFNB60 ARNSHL locus. Moreover, we performed whole-exome sequencing on FT13 patient DNA and uncovered aminoacid substitution p.Cys113Tyr in SLC22A4, a transporter of organic cations, cosegregating with HL in FT13 and therefore the cause of ARNSHL DFNB60. We also screened a cohort of small Tunisian HL families and uncovered an additional deaf proband of consanguineous parents that is homozygous for p.Cys113Tyr carried by the same microsatellite marker haplotype as in FT13, indicating that this mutation is ancestral. Using immunofluorescence, we found that Slc22a4 is expressed in stria vascularis (SV) endothelial cells of rodent cochlea and targets their apical plasma membrane. We also found Slc22a4 transcripts in our RNA-seq library from purified primary culture of mouse SV endothelial cells. Interestingly, p.Cys113Tyr mutation affects the trafficking of the transporter and severely alters Ergothioneine uptake. We conclude that SLC22A4 is an organic cation transporter of the SV endothelium that is essential for hearing, and its mutation causes DFNB60 form of HL. PMID:27023905

Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations | Office of Cancer Genomics

Cancer.gov

Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers.

KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy

PubMed Central

Ambrogio, Chiara; Nadal, Ernest; Villanueva, Alberto; Gómez-López, Gonzalo; Cash, Timothy P; Barbacid, Mariano; Santamaría, David

2016-01-01

Understanding the early evolution of cancer heterogeneity during the initial steps of tumorigenesis can uncover vulnerabilities of cancer cells that may be masked at later stages. We describe a comprehensive approach employing gene expression analysis in early lesions to identify novel therapeutic targets and the use of mouse models to test synthetic lethal drug combinations to treat human Kirsten rat sarcoma viral oncogene homologue (KRAS)-driven lung adenocarcinoma. PMID:27843638

Modeling Hydrological Extremes in the Anthropocene

NASA Astrophysics Data System (ADS)

Di Baldassarre, Giuliano; Martinez, Fabian; Kalantari, Zahra; Viglione, Alberto

2017-04-01

Hydrological studies have investigated human impacts on hydrological extremes, i.e. droughts and floods, while social studies have explored human responses and adaptation to them. Yet, there is still little understanding about the dynamics resulting from two-way feedbacks, i.e. both impacts and responses. Traditional risk assessment methods therefore fail to assess future dynamics, and thus risk reduction strategies built on these methods can lead to unintended consequences in the medium-long term. Here we review the dynamics resulting from the reciprocal links between society and hydrological extremes, and describe initial efforts to model floods and droughts in the Anthropocene. In particular, we first discuss the need for a novel approach to explicitly account for human interactions with both hydrological extremes, and then present a stylized model simulating the reciprocal effects between droughts, foods and reservoir operation rules. Unprecedented opportunities offered by the growing availability of global data and worldwide archives to uncover the mutual shaping of hydrological extremes and society across places and scales are also discussed.

Of Mice and Snakes: A Tail of Oct4.

PubMed

Shylo, Natalia A; Weatherbee, Scott D

2016-08-08

The vertebrate axial skeleton comprises regions of specialized vertebrae, which vary in length between lineages. Aires et al. (2016) uncover a key role for Oct4 in determining trunk length in mice. Additionally, a heterochronic shift in Oct4 expression may underlie the extreme elongation of the trunk in snakes. Copyright © 2016 Elsevier Inc. All rights reserved.

Reliability and validity of the Persian lower extremity functional scale (LEFS) in a heterogeneous sample of outpatients with lower limb musculoskeletal disorders.

PubMed

Negahban, Hossein; Hessam, Masumeh; Tabatabaei, Saeid; Salehi, Reza; Sohani, Soheil Mansour; Mehravar, Mohammad

2014-01-01

The aim was to culturally translate and validate the Persian lower extremity functional scale (LEFS) in a heterogeneous sample of outpatients with lower extremity musculoskeletal disorders (n = 304). This is a prospective methodological study. After a standard forward-backward translation, psychometric properties were assessed in terms of test-retest reliability, internal consistency, construct validity, dimensionality, and ceiling or floor effects. The acceptable level of intraclass correlation coefficient >0.70 and Cronbach's alpha coefficient >0.70 was obtained for the Persian LEFS. Correlations between Persian LEFS and Short-Form 36 Health Survey (SF-36) subscales of Physical Health component (rs range = 0.38-0.78) were higher than correlations between Persian LEFS and SF-36 subscales of Mental Health component (rs range = 0.15-0.39). A corrected item--total correlation of >0.40 (Spearman's rho) was obtained for all items of the Persian LEFS. Horn's parallel analysis detected a total of two factors. No ceiling or floor effects were detected for the Persian LEFS. The Persian version of the LEFS is a reliable and valid instrument that can be used to measure functional status in Persian-speaking patients with different musculoskeletal disorders of the lower extremity. Implications for Rehabilitation The Persian lower extremity functional scale (LEFS) is a reliable, internally consistent and valid instrument, with no ceiling or floor effects, to determine functional status of heterogeneous patients with musculoskeletal disorders of the lower extremity. The Persian version of the LEFS can be used in clinical and research settings to measure function in Iranian patients with different musculoskeletal disorders of the lower extremity.

A comprehensive analysis of 3′ end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogeneous ribonucleoprotein C on cleavage and polyadenylation

PubMed Central

Gruber, Andreas J.; Schmidt, Ralf; Gruber, Andreas R.; Martin, Georges; Ghosh, Souvik; Belmadani, Manuel; Keller, Walter

2016-01-01

Alternative polyadenylation (APA) is a general mechanism of transcript diversification in mammals, which has been recently linked to proliferative states and cancer. Different 3′ untranslated region (3′ UTR) isoforms interact with different RNA-binding proteins (RBPs), which modify the stability, translation, and subcellular localization of the corresponding transcripts. Although the heterogeneity of pre-mRNA 3′ end processing has been established with high-throughput approaches, the mechanisms that underlie systematic changes in 3′ UTR lengths remain to be characterized. Through a uniform analysis of a large number of 3′ end sequencing data sets, we have uncovered 18 signals, six of which are novel, whose positioning with respect to pre-mRNA cleavage sites indicates a role in pre-mRNA 3′ end processing in both mouse and human. With 3′ end sequencing we have demonstrated that the heterogeneous ribonucleoprotein C (HNRNPC), which binds the poly(U) motif whose frequency also peaks in the vicinity of polyadenylation (poly(A)) sites, has a genome-wide effect on poly(A) site usage. HNRNPC-regulated 3′ UTRs are enriched in ELAV-like RBP 1 (ELAVL1) binding sites and include those of the CD47 gene, which participate in the recently discovered mechanism of 3′ UTR–dependent protein localization (UDPL). Our study thus establishes an up-to-date, high-confidence catalog of 3′ end processing sites and poly(A) signals, and it uncovers an important role of HNRNPC in regulating 3′ end processing. It further suggests that U-rich elements mediate interactions with multiple RBPs that regulate different stages in a transcript's life cycle. PMID:27382025

Treatment of symptomatic coral reef aorta with an uncovered stent graft.

PubMed

Bosanquet, D C; Wood, A; Williams, I M

2015-10-01

Coral reef aorta is a rare condition characterised by extreme calcific growths affecting the juxta and suprarenal aorta. It can cause symptoms due to visceral ischaemia, lower limb hypoperfusion, and distal embolisation. We present a case of a 61-year-old man with unresponsive hypertension, who was found to have an occluded right renal artery, and an extensive coral reef aorta with a marked pressure gradient across the lesion. Renal hypoperfusion secondary to aortic coral reef aorta was thought to be the cause for his hypertension. Endovascular placement of a balloon expandable uncovered stent resolved his hypertension within one month, with no adverse effects noted at subsequent follow-up. Endovascular treatment of coral reef aorta is technically possible and avoids a major vascular procedure. © The Author(s) 2014.

Uncovering hidden heterogeneity: Geo-statistical models illuminate the fine scale effects of boating infrastructure on sediment characteristics and contaminants.

PubMed

Hedge, L H; Dafforn, K A; Simpson, S L; Johnston, E L

2017-06-30

Infrastructure associated with coastal communities is likely to not only directly displace natural systems, but also leave environmental footprints' that stretch over multiple scales. Some coastal infrastructure will, there- fore, generate a hidden layer of habitat heterogeneity in sediment systems that is not immediately observable in classical impact assessment frameworks. We examine the hidden heterogeneity associated with one of the most ubiquitous coastal modifications; dense swing moorings fields. Using a model based geo-statistical framework we highlight the variation in sedimentology throughout mooring fields and reference locations. Moorings were correlated with patches of sediment with larger particle sizes, and associated metal(loid) concentrations in these patches were depressed. Our work highlights two important ideas i) mooring fields create a mosaic of habitat in which contamination decreases and grain sizes increase close to moorings, and ii) model- based frameworks provide an information rich, easy-to-interpret way to communicate complex analyses to stakeholders. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Control of epidemics on complex networks: Effectiveness of delayed isolation

NASA Astrophysics Data System (ADS)

Pereira, Tiago; Young, Lai-Sang

2015-08-01

We study isolation as a means to control epidemic outbreaks in complex networks, focusing on the consequences of delays in isolating infected nodes. Our analysis uncovers a tipping point: if infected nodes are isolated before a critical day dc, the disease is effectively controlled, whereas for longer delays the number of infected nodes climbs steeply. We show that dc can be estimated explicitly in terms of network properties and disease parameters, connecting lowered values of dc explicitly to heterogeneity in degree distribution. Our results reveal also that initial delays in the implementation of isolation protocols can have catastrophic consequences in heterogeneous networks. As our study is carried out in a general framework, it has the potential to offer insight and suggest proactive strategies for containing outbreaks of a range of serious infectious diseases.

Heterogeneity and O-16-Enrichments in Oxygen Isotope Ratios of Olivine from Chondrules in the Mokoia CV3 Chondrite

NASA Technical Reports Server (NTRS)

Jones, R. H.; Leshin, L. A.; Guan, Y.

2002-01-01

Two chondrules from Mokoia contain olivine in which oxygen isotopes are extremely heterogeneous, with some grains highly enriched in O-16. These data provide an important link between CAIs and chondrules. Additional information is contained in the original extended abstract.

Multiple Kernel Learning for Heterogeneous Anomaly Detection: Algorithm and Aviation Safety Case Study

NASA Technical Reports Server (NTRS)

Das, Santanu; Srivastava, Ashok N.; Matthews, Bryan L.; Oza, Nikunj C.

2010-01-01

The world-wide aviation system is one of the most complex dynamical systems ever developed and is generating data at an extremely rapid rate. Most modern commercial aircraft record several hundred flight parameters including information from the guidance, navigation, and control systems, the avionics and propulsion systems, and the pilot inputs into the aircraft. These parameters may be continuous measurements or binary or categorical measurements recorded in one second intervals for the duration of the flight. Currently, most approaches to aviation safety are reactive, meaning that they are designed to react to an aviation safety incident or accident. In this paper, we discuss a novel approach based on the theory of multiple kernel learning to detect potential safety anomalies in very large data bases of discrete and continuous data from world-wide operations of commercial fleets. We pose a general anomaly detection problem which includes both discrete and continuous data streams, where we assume that the discrete streams have a causal influence on the continuous streams. We also assume that atypical sequence of events in the discrete streams can lead to off-nominal system performance. We discuss the application domain, novel algorithms, and also discuss results on real-world data sets. Our algorithm uncovers operationally significant events in high dimensional data streams in the aviation industry which are not detectable using state of the art methods

Identifying and Assessing Interesting Subgroups in a Heterogeneous Population.

PubMed

Lee, Woojoo; Alexeyenko, Andrey; Pernemalm, Maria; Guegan, Justine; Dessen, Philippe; Lazar, Vladimir; Lehtiö, Janne; Pawitan, Yudi

2015-01-01

Biological heterogeneity is common in many diseases and it is often the reason for therapeutic failures. Thus, there is great interest in classifying a disease into subtypes that have clinical significance in terms of prognosis or therapy response. One of the most popular methods to uncover unrecognized subtypes is cluster analysis. However, classical clustering methods such as k-means clustering or hierarchical clustering are not guaranteed to produce clinically interesting subtypes. This could be because the main statistical variability--the basis of cluster generation--is dominated by genes not associated with the clinical phenotype of interest. Furthermore, a strong prognostic factor might be relevant for a certain subgroup but not for the whole population; thus an analysis of the whole sample may not reveal this prognostic factor. To address these problems we investigate methods to identify and assess clinically interesting subgroups in a heterogeneous population. The identification step uses a clustering algorithm and to assess significance we use a false discovery rate- (FDR-) based measure. Under the heterogeneity condition the standard FDR estimate is shown to overestimate the true FDR value, but this is remedied by an improved FDR estimation procedure. As illustrations, two real data examples from gene expression studies of lung cancer are provided.

Pointwise mutual information quantifies intratumor heterogeneity in tissue sections labeled with multiple fluorescent biomarkers.

PubMed

Spagnolo, Daniel M; Gyanchandani, Rekha; Al-Kofahi, Yousef; Stern, Andrew M; Lezon, Timothy R; Gough, Albert; Meyer, Dan E; Ginty, Fiona; Sarachan, Brion; Fine, Jeffrey; Lee, Adrian V; Taylor, D Lansing; Chennubhotla, S Chakra

2016-01-01

Measures of spatial intratumor heterogeneity are potentially important diagnostic biomarkers for cancer progression, proliferation, and response to therapy. Spatial relationships among cells including cancer and stromal cells in the tumor microenvironment (TME) are key contributors to heterogeneity. We demonstrate how to quantify spatial heterogeneity from immunofluorescence pathology samples, using a set of 3 basic breast cancer biomarkers as a test case. We learn a set of dominant biomarker intensity patterns and map the spatial distribution of the biomarker patterns with a network. We then describe the pairwise association statistics for each pattern within the network using pointwise mutual information (PMI) and visually represent heterogeneity with a two-dimensional map. We found a salient set of 8 biomarker patterns to describe cellular phenotypes from a tissue microarray cohort containing 4 different breast cancer subtypes. After computing PMI for each pair of biomarker patterns in each patient and tumor replicate, we visualize the interactions that contribute to the resulting association statistics. Then, we demonstrate the potential for using PMI as a diagnostic biomarker, by comparing PMI maps and heterogeneity scores from patients across the 4 different cancer subtypes. Estrogen receptor positive invasive lobular carcinoma patient, AL13-6, exhibited the highest heterogeneity score among those tested, while estrogen receptor negative invasive ductal carcinoma patient, AL13-14, exhibited the lowest heterogeneity score. This paper presents an approach for describing intratumor heterogeneity, in a quantitative fashion (via PMI), which departs from the purely qualitative approaches currently used in the clinic. PMI is generalizable to highly multiplexed/hyperplexed immunofluorescence images, as well as spatial data from complementary in situ methods including FISSEQ and CyTOF, sampling many different components within the TME. We hypothesize that PMI will uncover key spatial interactions in the TME that contribute to disease proliferation and progression.

Uncovering Heavily Obscured AGN with WISE and NuSTAR

NASA Astrophysics Data System (ADS)

Hickox, Ryan C.; Carroll, Christopher M.; Yan, Wei; DiPompeo, Michael A.; Hainline, Kevin N.; NuSTAR Obscured AGN Team

2018-01-01

Supermassive black holes gain their mass through accretion as active galactic nuclei (AGN), but it is now clear that a large fraction of this growth is "hidden" behind large columns of gas and dust. Of particular interest are Compton-thick (CT) AGN, with columns NH > 1024 cm-2, that have been difficult to identify using optical or soft X-ray surveys. We will present two studies of heavily obscured AGN that aim to uncover more of the full population of "hidden" growing black holes: (1) Analysis of the spectral energy distributions of millions of galaxies with photometry from WISE (mid-IR), UKIDSS (near-IR), and SDSS (optical), that uncovers large populations of weak or heavily buried AGN, and (2) NuSTAR observations of a sample of candidate highly obscured AGN, selected from WISE and SDSS photometry,and confirmed using SALT and Keck spectroscopy. The NuSTAR data reveal the existence of powerful CT quasars with extremely large columns NH > 1025 cm-2, which may represent a significant fraction of previously hidden black hole growth. This work is supported by NASA grant numbers NNX16AN48G and NNX15AP24G, and the NSF through grant numbers 1515364 and 1554584.

Extreme rainfall, vulnerability and risk: a continental-scale assessment for South America.

PubMed

Vörösmarty, Charles J; Bravo de Guenni, Lelys; Wollheim, Wilfred M; Pellerin, Brian; Bjerklie, David; Cardoso, Manoel; D'Almeida, Cassiano; Green, Pamela; Colon, Lilybeth

2013-11-13

Extreme weather continues to preoccupy society as a formidable public safety concern bearing huge economic costs. While attention has focused on global climate change and how it could intensify key elements of the water cycle such as precipitation and river discharge, it is the conjunction of geophysical and socioeconomic forces that shapes human sensitivity and risks to weather extremes. We demonstrate here the use of high-resolution geophysical and population datasets together with documentary reports of rainfall-induced damage across South America over a multi-decadal, retrospective time domain (1960-2000). We define and map extreme precipitation hazard, exposure, affectedpopulations, vulnerability and risk, and use these variables to analyse the impact of floods as a water security issue. Geospatial experiments uncover major sources of risk from natural climate variability and population growth, with change in climate extremes bearing a minor role. While rural populations display greatest relative sensitivity to extreme rainfall, urban settings show the highest rates of increasing risk. In the coming decades, rapid urbanization will make South American cities the focal point of future climate threats but also an opportunity for reducing vulnerability, protecting lives and sustaining economic development through both traditional and ecosystem-based disaster risk management systems.

Uncovering the role of the East Asian jet stream and heterogeneities in atmospheric rivers affecting the western United States.

PubMed

Zhang, Wei; Villarini, Gabriele

2018-01-30

Atmospheric rivers (ARs) exert major socioeconomic repercussions along the US West Coast by inducing heavy rainfall, flooding, strong winds, and storm surge. Despite the significant societal and economic repercussions of these storms, our understanding of the physical drivers responsible for their interannual variability is limited, with different climate modes identified as possible mechanisms. Here we show that the Pacific-Japan (PJ) teleconnections/patterns and the East Asian subtropical jet (EASJ) exhibit a strong linkage with the total frequency of ARs making landfall over the western United States, much stronger than the other potential climate modes previously considered. While our findings indicate that the PJ pattern and EASJ are the most relevant climate modes driving the overall AR activity, we also uncover heterogeneities in AR tracks. Specifically, we show that not all ARs making landfall along the West Coast come from a single population, but rather that it is possible to stratify these storms into three clusters. While the PJ pattern and EASJ are major drivers of AR activity for two clusters, the cluster that primarily affects the US Southwest is largely driven by other climate modes [El Niño Southern Oscillation (ENSO), the Atlantic meridional mode (AMM), the Pacific-North America (PNA) teleconnection pattern, and the North Pacific Gyre Oscillation (NPGO)]. Therefore, important regional differences exist and this information can substantially enhance our ability to predict and prepare for these storms and their impacts.

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing

PubMed Central

Radovich, Milan; Clare, Susan E.; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A.; Solzak, Jeffrey P.; Kassem, Nawal; Mathieson, Theresa; Storniolo, Anna Maria V.; Rufenbarger, Connie; Lillemoe, Heather A.; Blosser, Rachel J.; Choi, Mi Ran; Sauder, Candice A.; Doxey, Diane; Henry, Jill E.; Hilligoss, Eric E.; Sakarya, Onur; Hyland, Fiona C.; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W.; Schneider, Bryan P.

2014-01-01

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER−,PR−,HER2−). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90% of TNBCs revealing an over-expressed central network. In conclusion, Use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos. PMID:24292813

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing.

PubMed

Radovich, Milan; Clare, Susan E; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A; Solzak, Jeffrey P; Kassem, Nawal; Mathieson, Theresa; Storniolo, Anna Maria V; Rufenbarger, Connie; Lillemoe, Heather A; Blosser, Rachel J; Choi, Mi Ran; Sauder, Candice A; Doxey, Diane; Henry, Jill E; Hilligoss, Eric E; Sakarya, Onur; Hyland, Fiona C; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W; Schneider, Bryan P

2014-01-01

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.

The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation.

PubMed

Buratti, Emanuele; Baralle, Francisco Ernesto

2010-01-01

Heterogeneous ribonucleoproteins (hnRNPs) are multifunctional RNA-binding proteins (RBPs) involved in many cellular processes. They participate in most gene expression pathways, from DNA replication and repair to mRNA translation. Among this class of proteins, TDP-43 (and more recently FUS/TLS) have received considerable attention due to their involvement in several neurodegenerative diseases. This finding has prompted many research groups to focus on the gene expression pathways that are regulated by these proteins. The results have uncovered a considerable complexity of TDP-43 and FUS/TLS functions due to the many independent mechanisms by which they may act to influence various cellular processes (such as DNA transcription, pre-mRNA splicing, mRNA export/import). The aim of this chapter will be to review especially some of the novel functions that have been uncovered, such as role in miRNA synthesis, regulation of transcript levels, and potential autoregulatory mechanisms in order to provide the basis for further investigations.

Systematic analysis of transcription start sites in avian development.

PubMed

Lizio, Marina; Deviatiiarov, Ruslan; Nagai, Hiroki; Galan, Laura; Arner, Erik; Itoh, Masayoshi; Lassmann, Timo; Kasukawa, Takeya; Hasegawa, Akira; Ros, Marian A; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R; Kawaji, Hideya; Gusev, Oleg; Sheng, Guojun

2017-09-01

Cap Analysis of Gene Expression (CAGE) in combination with single-molecule sequencing technology allows precision mapping of transcription start sites (TSSs) and genome-wide capture of promoter activities in differentiated and steady state cell populations. Much less is known about whether TSS profiling can characterize diverse and non-steady state cell populations, such as the approximately 400 transitory and heterogeneous cell types that arise during ontogeny of vertebrate animals. To gain such insight, we used the chick model and performed CAGE-based TSS analysis on embryonic samples covering the full 3-week developmental period. In total, 31,863 robust TSS peaks (>1 tag per million [TPM]) were mapped to the latest chicken genome assembly, of which 34% to 46% were active in any given developmental stage. ZENBU, a web-based, open-source platform, was used for interactive data exploration. TSSs of genes critical for lineage differentiation could be precisely mapped and their activities tracked throughout development, suggesting that non-steady state and heterogeneous cell populations are amenable to CAGE-based transcriptional analysis. Our study also uncovered a large set of extremely stable housekeeping TSSs and many novel stage-specific ones. We furthermore demonstrated that TSS mapping could expedite motif-based promoter analysis for regulatory modules associated with stage-specific and housekeeping genes. Finally, using Brachyury as an example, we provide evidence that precise TSS mapping in combination with Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-on technology enables us, for the first time, to efficiently target endogenous avian genes for transcriptional activation. Taken together, our results represent the first report of genome-wide TSS mapping in birds and the first systematic developmental TSS analysis in any amniote species (birds and mammals). By facilitating promoter-based molecular analysis and genetic manipulation, our work also underscores the value of avian models in unravelling the complex regulatory mechanism of cell lineage specification during amniote development.

Countering Terrorism on Military Installations

DTIC Science & Technology

1977-07-29

military forces and police agencies since 1970 uncover fanc - tional task-areas which require examinatiin subsequent to development of theory (policy...with the CinC in his office. GEN Blanchard was aware of the ’AI visit and had reqiiested this meeting. He was extremely interested and knowledgeable in...the subject of te:’rorism. He had recettly directed the Provost Marshal to prepare a paper on the subject and a command regulation. GEN Blanchard re

Ultra-Bright Optical Transients Are Linked With Type Ic Supernovae

DTIC Science & Technology

2010-11-20

Station, Flagstaff, AZ 86001, USA Received 2010 August 16; accepted 2010 September 9; published 2010 October 25 ABSTRACT Recent searches by unbiased...wide-field surveys have uncovered a group of extremely luminous optical transients. The initial discoveries of SN 2005ap by the Texas Supernova Search ...supernova searches (e.g., the Texas Supernova Search ) or all-sky surveys, such as the Panoramic Survey Telescope & Rapid Response System (Pan-STARRS), the

Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis.

PubMed

Cochain, Clément; Vafadarnejad, Ehsan; Arampatzi, Panagiota; Jaroslav, Pelisek; Winkels, Holger; Ley, Klaus; Wolf, Dennis; Saliba, Antoine-Emmanuel; Zernecke, Alma

2018-03-15

Rationale: It is assumed that atherosclerotic arteries contain several macrophage subsets endowed with specific functions. The precise identity of these subsets is poorly characterized as they ha ve been defined by the expression of a restricted number of markers. Objective: We have applied single-cell RNA-seq as an unbiased profiling strategy to interrogate and classify aortic macrophage heterogeneity at the single-cell level in atherosclerosis. Methods and Results: We performed single-cell RNA sequencing of total aortic CD45 + cells extracted from the non-diseased (chow fed) and atherosclerotic (11 weeks of high fat diet) aorta of Ldlr -/- mice. Unsupervised clustering singled out 13 distinct aortic cell clusters. Among the myeloid cell populations, Resident-like macrophages with a gene expression profile similar to aortic resident macrophages were found in healthy and diseased aortae, whereas monocytes, monocyte-derived dendritic cells (MoDC), and two populations of macrophages were almost exclusively detectable in atherosclerotic aortae, comprising Inflammatory macrophages showing enrichment in I l1b , and previously undescribed TREM2 hi macrophages. Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns distinguishing these three macrophage subsets and MoDC, and uncovered putative functions of each cell type. Notably, TREM2 hi macrophages appeared to be endowed with specialized functions in lipid metabolism and catabolism, and presented a gene expression signature reminiscent of osteoclasts, suggesting a role in lesion calcification. TREM2 expression was moreover detected in human lesional macrophages. Importantly, these macrophage populations were present also in advanced atherosclerosis and in Apoe -/- aortae, indicating relevance of our findings in different stages of atherosclerosis and mouse models. Conclusions: These data unprecedentedly uncovered the transcriptional landscape and phenotypic heterogeneity of aortic macrophages and MoDCs in atherosclerotic and identified previously unrecognized macrophage populations and their gene expression signature, suggesting specialized functions. Our findings will open up novel opportunities to explore distinct myeloid cell populations and their functions in atherosclerosis.

Chapter 12: The variable-density thinning study at Stanislaus-Tuolumne Experimental Forest

Treesearch

E. Knapp; M. North; M. Benech; B. Estes

2012-01-01

Prior to historical logging and fire suppression, forests of the Sierra Nevada were extremely heterogeneous. Frequent low- to moderate-intensity fire was partly responsible for this heterogeneity, which in turn helped make forests resilient to high-severity stand-replacing events. Early observers of forests on the west slope of the Sierra Nevada noted the...

Ownership and ecosystem as sources of spatial heterogeneity in a forested landscape, Wisconsin, USA

Treesearch

Thomas R. Crow; George E. Host; David J. Mladenoff

1999-01-01

The interaction between physical environment and land ownership in creating spatial heterogeneity was studied in largely forested landscapes of northern Wisconsin, USA. A stratified random approach was used in which 2500-ha plots representing two ownerships (National Forest and private non-industrial) were located within two regional ecosystems (extremely well-drained...

Why do some people do "more" to mitigate climate change than others? Exploring heterogeneity in psycho-social associations.

PubMed

Ortega-Egea, José Manuel; García-de-Frutos, Nieves; Antolín-López, Raquel

2014-01-01

The urgency of climate change mitigation calls for a profound shift in personal behavior. This paper investigates psycho-social correlates of extra mitigation behavior in response to climate change, while also testing for potential (unobserved) heterogeneity in European citizens' decision-making. A person's extra mitigation behavior in response to climate change is conceptualized--and differentiated from common mitigation behavior--as some people's broader and greater levels of behavioral engagement (compared to others) across specific self-reported mitigation actions and behavioral domains. Regression analyses highlight the importance of environmental psychographics (i.e., attitudes, motivations, and knowledge about climate change) and socio-demographics (especially country-level variables) in understanding extra mitigation behavior. By looking at the data through the lens of segmentation, significant heterogeneity is uncovered in the associations of attitudes and knowledge about climate change--but not in motivational or socio-demographic links--with extra mitigation behavior in response to climate change, across two groups of environmentally active respondents. The study has implications for promoting more ambitious behavioral responses to climate change, both at the individual level and across countries.

Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing.

PubMed

Tang, Qin; Iyer, Sowmya; Lobbardi, Riadh; Moore, John C; Chen, Huidong; Lareau, Caleb; Hebert, Christine; Shaw, McKenzie L; Neftel, Cyril; Suva, Mario L; Ceol, Craig J; Bernards, Andre; Aryee, Martin; Pinello, Luca; Drummond, Iain A; Langenau, David M

2017-10-02

Recent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA-protein kinase catalytic subunit ( prkdc ), interleukin-2 receptor γ a ( il2rga ), and double-homozygous-mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants. Our analysis also uncovered novel cell types, including two classes of natural killer immune cells, classically defined and erythroid-primed hematopoietic stem and progenitor cells, mucin-secreting kidney cells, and kidney stem/progenitor cells. In total, our work provides the first, comprehensive, single-cell, transcriptomic analysis of kidney and marrow cells in the adult zebrafish. © 2017 Tang et al.

Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing

PubMed Central

Iyer, Sowmya; Lobbardi, Riadh; Chen, Huidong; Hebert, Christine; Shaw, McKenzie L.; Neftel, Cyril; Suva, Mario L.; Bernards, Andre; Aryee, Martin; Drummond, Iain A.

2017-01-01

Recent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA–protein kinase catalytic subunit (prkdc), interleukin-2 receptor γ a (il2rga), and double-homozygous–mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants. Our analysis also uncovered novel cell types, including two classes of natural killer immune cells, classically defined and erythroid-primed hematopoietic stem and progenitor cells, mucin-secreting kidney cells, and kidney stem/progenitor cells. In total, our work provides the first, comprehensive, single-cell, transcriptomic analysis of kidney and marrow cells in the adult zebrafish. PMID:28878000

Science & Technology Review September/October 2008

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bearinger, J P

2008-07-21

This issue has the following articles: (1) Answering Scientists Most Audacious Questions--Commentary by Dona Crawford; (2) Testing the Accuracy of the Supernova Yardstick--High-resolution simulations are advancing understanding of Type Ia supernovae to help uncover the mysteries of dark energy; (3) Developing New Drugs and Personalized Medical Treatment--Accelerator mass spectrometry is emerging as an essential tool for assessing the effects of drugs in humans; (4) Triage in a Patch--A painless skin patch and accompanying detector can quickly indicate human exposure to biological pathogens, chemicals, explosives, or radiation; and (5) Smoothing Out Defects for Extreme Ultraviolet Lithography--A process for smoothing mask defectsmore » helps move extreme ultraviolet lithography one step closer to creating smaller, more powerful computer chips.« less

Extremely Luminous Far-infrared Sources (ELFS)

NASA Technical Reports Server (NTRS)

Harwit, Martin; Houck, James R.; Soifer, B. Thomas; Palumbo, Giorgio G. C.

1987-01-01

The Infrared Astronomical Satellite (IRAS) survey uncovered a class of Extremely Luminous Far Infrared Sources (ELFS), exhibiting luminosities up to and occasionally exceeding 10 to the 12th power L sub 0. Arguments are presented to show that sources with luminosities L equal to or greater than 3 x 10 to the 10th power L sub 0 may represent gas rich galaxies in collision. The more conventional explanation of these sources as sites of extremely active star formation fails to explain the observed low optical luminosities of ELFS as well as their high infrared excess. In contrast, a collisional model heats gas to a temperature of approx. 10 to the 6th power K where cooling takes place in the extreme ultraviolet. The UV is absorbed by dust and converted into far infrared radiation (FIR) without generation of appreciable optical luminosity. Gas recombination as it cools generates a Lyman alpha photon only once for every two extreme ultraviolet approx. 50eV photons emitted by the 10 to the 6th power gas. That accounts for the high infrared excess. Finally, the model also is able to explain the observed luminosity distribution of ELFS as well as many other traits.

HGIMDA: Heterogeneous graph inference for miRNA-disease association prediction

PubMed Central

Zhang, Xu; You, Zhu-Hong; Huang, Yu-An; Yan, Gui-Ying

2016-01-01

Recently, microRNAs (miRNAs) have drawn more and more attentions because accumulating experimental studies have indicated miRNA could play critical roles in multiple biological processes as well as the development and progression of human complex diseases. Using the huge number of known heterogeneous biological datasets to predict potential associations between miRNAs and diseases is an important topic in the field of biology, medicine, and bioinformatics. In this study, considering the limitations in the previous computational methods, we developed the computational model of Heterogeneous Graph Inference for MiRNA-Disease Association prediction (HGIMDA) to uncover potential miRNA-disease associations by integrating miRNA functional similarity, disease semantic similarity, Gaussian interaction profile kernel similarity, and experimentally verified miRNA-disease associations into a heterogeneous graph. HGIMDA obtained AUCs of 0.8781 and 0.8077 based on global and local leave-one-out cross validation, respectively. Furthermore, HGIMDA was applied to three important human cancers for performance evaluation. As a result, 90% (Colon Neoplasms), 88% (Esophageal Neoplasms) and 88% (Kidney Neoplasms) of top 50 predicted miRNAs are confirmed by recent experiment reports. Furthermore, HGIMDA could be effectively applied to new diseases and new miRNAs without any known associations, which overcome the important limitations of many previous computational models. PMID:27533456

HGIMDA: Heterogeneous graph inference for miRNA-disease association prediction.

PubMed

Chen, Xing; Yan, Chenggang Clarence; Zhang, Xu; You, Zhu-Hong; Huang, Yu-An; Yan, Gui-Ying

2016-10-04

Recently, microRNAs (miRNAs) have drawn more and more attentions because accumulating experimental studies have indicated miRNA could play critical roles in multiple biological processes as well as the development and progression of human complex diseases. Using the huge number of known heterogeneous biological datasets to predict potential associations between miRNAs and diseases is an important topic in the field of biology, medicine, and bioinformatics. In this study, considering the limitations in the previous computational methods, we developed the computational model of Heterogeneous Graph Inference for MiRNA-Disease Association prediction (HGIMDA) to uncover potential miRNA-disease associations by integrating miRNA functional similarity, disease semantic similarity, Gaussian interaction profile kernel similarity, and experimentally verified miRNA-disease associations into a heterogeneous graph. HGIMDA obtained AUCs of 0.8781 and 0.8077 based on global and local leave-one-out cross validation, respectively. Furthermore, HGIMDA was applied to three important human cancers for performance evaluation. As a result, 90% (Colon Neoplasms), 88% (Esophageal Neoplasms) and 88% (Kidney Neoplasms) of top 50 predicted miRNAs are confirmed by recent experiment reports. Furthermore, HGIMDA could be effectively applied to new diseases and new miRNAs without any known associations, which overcome the important limitations of many previous computational models.

Identifying and Assessing Interesting Subgroups in a Heterogeneous Population

PubMed Central

Lee, Woojoo; Alexeyenko, Andrey; Pernemalm, Maria; Guegan, Justine; Dessen, Philippe; Lazar, Vladimir; Lehtiö, Janne; Pawitan, Yudi

2015-01-01

Biological heterogeneity is common in many diseases and it is often the reason for therapeutic failures. Thus, there is great interest in classifying a disease into subtypes that have clinical significance in terms of prognosis or therapy response. One of the most popular methods to uncover unrecognized subtypes is cluster analysis. However, classical clustering methods such as k-means clustering or hierarchical clustering are not guaranteed to produce clinically interesting subtypes. This could be because the main statistical variability—the basis of cluster generation—is dominated by genes not associated with the clinical phenotype of interest. Furthermore, a strong prognostic factor might be relevant for a certain subgroup but not for the whole population; thus an analysis of the whole sample may not reveal this prognostic factor. To address these problems we investigate methods to identify and assess clinically interesting subgroups in a heterogeneous population. The identification step uses a clustering algorithm and to assess significance we use a false discovery rate- (FDR-) based measure. Under the heterogeneity condition the standard FDR estimate is shown to overestimate the true FDR value, but this is remedied by an improved FDR estimation procedure. As illustrations, two real data examples from gene expression studies of lung cancer are provided. PMID:26339613

Regression and Data Mining Methods for Analyses of Multiple Rare Variants in the Genetic Analysis Workshop 17 Mini-Exome Data

PubMed Central

Bailey-Wilson, Joan E.; Brennan, Jennifer S.; Bull, Shelley B; Culverhouse, Robert; Kim, Yoonhee; Jiang, Yuan; Jung, Jeesun; Li, Qing; Lamina, Claudia; Liu, Ying; Mägi, Reedik; Niu, Yue S.; Simpson, Claire L.; Wang, Libo; Yilmaz, Yildiz E.; Zhang, Heping; Zhang, Zhaogong

2012-01-01

Group 14 of Genetic Analysis Workshop 17 examined several issues related to analysis of complex traits using DNA sequence data. These issues included novel methods for analyzing rare genetic variants in an aggregated manner (often termed collapsing rare variants), evaluation of various study designs to increase power to detect effects of rare variants, and the use of machine learning approaches to model highly complex heterogeneous traits. Various published and novel methods for analyzing traits with extreme locus and allelic heterogeneity were applied to the simulated quantitative and disease phenotypes. Overall, we conclude that power is (as expected) dependent on locus-specific heritability or contribution to disease risk, large samples will be required to detect rare causal variants with small effect sizes, extreme phenotype sampling designs may increase power for smaller laboratory costs, methods that allow joint analysis of multiple variants per gene or pathway are more powerful in general than analyses of individual rare variants, population-specific analyses can be optimal when different subpopulations harbor private causal mutations, and machine learning methods may be useful for selecting subsets of predictors for follow-up in the presence of extreme locus heterogeneity and large numbers of potential predictors. PMID:22128066

Extreme rainfall, vulnerability and risk: a continental-scale assessment for South America

USGS Publications Warehouse

Vorosmarty, Charles J.; de Guenni, Lelys Bravo; Wollheim, Wilfred M.; Pellerin, Brian A.; Bjerklie, David M.; Cardoso, Manoel; D'Almeida, Cassiano; Colon, Lilybeth

2013-01-01

Extreme weather continues to preoccupy society as a formidable public safety concern bearing huge economic costs. While attention has focused on global climate change and how it could intensify key elements of the water cycle such as precipitation and river discharge, it is the conjunction of geophysical and socioeconomic forces that shapes human sensitivity and risks to weather extremes. We demonstrate here the use of high-resolution geophysical and population datasets together with documentary reports of rainfall-induced damage across South America over a multi-decadal, retrospective time domain (1960–2000). We define and map extreme precipitation hazard, exposure, affectedpopulations, vulnerability and risk, and use these variables to analyse the impact of floods as a water security issue. Geospatial experiments uncover major sources of risk from natural climate variability and population growth, with change in climate extremes bearing a minor role. While rural populations display greatest relative sensitivity to extreme rainfall, urban settings show the highest rates of increasing risk. In the coming decades, rapid urbanization will make South American cities the focal point of future climate threats but also an opportunity for reducing vulnerability, protecting lives and sustaining economic development through both traditional and ecosystem-based disaster risk management systems.

Imaging metabolic heterogeneity in cancer.

PubMed

Sengupta, Debanti; Pratx, Guillem

2016-01-06

As our knowledge of cancer metabolism has increased, it has become apparent that cancer metabolic processes are extremely heterogeneous. The reasons behind this heterogeneity include genetic diversity, the existence of multiple and redundant metabolic pathways, altered microenvironmental conditions, and so on. As a result, methods in the clinic and beyond have been developed in order to image and study tumor metabolism in the in vivo and in vitro regimes. Both regimes provide unique advantages and challenges, and may be used to provide a picture of tumor metabolic heterogeneity that is spatially and temporally comprehensive. Taken together, these methods may hold the key to appropriate cancer diagnoses and treatments in the future.

Understanding Heterogeneity in the Effects of Birth Weight on Adult Cognition and Wages

PubMed Central

Cook, C. Justin; Fletcher, Jason M.

2015-01-01

A large economics literature has shown long term impacts of birth weight on adult outcomes, including IQ and earnings that are often robust to sibling or twin fixed effects. We examine potential mechanisms underlying these effects by incorporating findings from the genetics and neuroscience literatures. We use a sample of siblings combined with an “orchids and dandelions hypothesis”, where the IQ of genetic dandelions is not affected by in utero nutrition variation but genetic orchids thrive under advantageous conditions and wilt in poor conditions. Indeed, using variation in three candidate genes related to neuroplasticity (APOE, BDNF, and COMT), we find substantial heterogeneity in the associations between birth weight and adult outcomes, where part of the population (i.e., “dandelions”) is not affected by birth weight variation. Our results help uncover why birth weight affects adult outcomes. PMID:25770970

Resolving ultrafast exciton migration in organic solids at the nanoscale

NASA Astrophysics Data System (ADS)

Ginsberg, Naomi

The migration of Frenkel excitons, tightly-bound electron-hole pairs, in photosynthesis and in organic semiconducting films is critical to the efficiency of natural and artificial light harvesting. While these materials exhibit a high degree of structural heterogeneity on the nanoscale, traditional measurements of exciton migration lengths are performed on bulk samples. Since both the characteristic length scales of structural heterogeneity and the reported bulk diffusion lengths are smaller than the optical diffraction limit, we adapt far-field super-resolution fluorescence imaging to uncover the correlations between the structural and energetic landscapes that the excitons explore. By combining the ultrafast super-resolved measurements with exciton hopping simulations we furthermore specify the nature (in addition to the extent) of exciton migration as a function of the intrinsic and ensemble chromophore energy scales that determine a spatio-energetic landscape for migration. In collaboration with: Samuel Penwell, Lucas Ginsberg, University of California, Berkeley and Rodrigo Noriega University of Utah.

Time-Resolved and Operando XAS Studies on Heterogeneous Catalysts - From the Gas Phase Towards Reactions in Supercritical Fluids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grunwaldt, Jan-Dierk; Baiker, Alfons

2007-02-02

x-ray absorption spectroscopy is a well-suited technique to uncover the structure of heterogeneous catalysts under reaction conditions. Different aspects of in situ cell design suitable for dynamic and catalytic studies are discussed. In addition, criteria are presented that allow estimating the influence external and internal mass transfer. Starting with studies on gas-solid reactions, including structure-activity relationships, this concept is extended to liquid-solid reactions, reactions at high pressure and in supercritical fluids. The following examples are discussed in more detail: partial oxidation of methane over Pt-Rh/Al2O3, reduction of a Cu/ZnO catalyst, alcohol oxidation over Bi-promoted Pd/Al2O3 in liquid phase and overmore » Pd/Al2O3 in supercritical CO2, and batch reactions (e.g. CO2-fixation over zinc-based catalysts)« less

Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib.

PubMed

Hoogstraat, Marlous; Gadellaa-van Hooijdonk, Christa G; Ubink, Inge; Besselink, Nicolle J M; Pieterse, Mark; Veldhuis, Wouter; van Stralen, Marijn; Meijer, Eelco F J; Willems, Stefan M; Hadders, Michael A; Kuilman, Thomas; Krijgsman, Oscar; Peeper, Daniel S; Koudijs, Marco J; Cuppen, Edwin; Voest, Emile E; Lolkema, Martijn P

2015-05-01

Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Understanding heterogeneity in the effects of birth weight on adult cognition and wages.

PubMed

Justin Cook, C; Fletcher, Jason M

2015-05-01

A large economics literature has shown long term impacts of birth weight on adult outcomes, including IQ and earnings that are often robust to sibling or twin fixed effects. We examine potential mechanisms underlying these effects by incorporating findings from the genetics and neuroscience literatures. We use a sample of siblings combined with an "orchids and dandelions hypothesis", where the IQ of genetic dandelions is not affected by in utero nutrition variation but genetic orchids thrive under advantageous conditions and wilt in poor conditions. Indeed, using variation in three candidate genes related to neuroplasticity (APOE, BDNF, and COMT), we find substantial heterogeneity in the associations between birth weight and adult outcomes, where part of the population (i.e., "dandelions") is not affected by birth weight variation. Our results help uncover why birth weight affects adult outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.

Simulations of Sulfate-Nitrate-Ammonium (SNA) aerosols during the extreme haze events over Northern China in October 2014

NASA Astrophysics Data System (ADS)

Chen, D.; Liu, Z.; Fast, J. D.; Ban, J.

2017-12-01

Extreme haze events have occurred frequently over China in recent years. Although many studies have investigated the formation mechanisms associated with PM2.5 for heavily polluted regions in China based on observational data, adequately predicting peak PM2.5 concentrations is still challenging for regional air quality models. In this study, we evaluate the performance of one configuration of the Weather Research and Forecasting model coupled with chemistry (WRF-Chem) and use the model to investigate the sensitivity of heterogeneous reactions on simulated peak sulfate, nitrate, and ammonium concentrations in the vicinity of Beijing during four extreme haze episodes in October 2014 over the North China Plain. The highest observed PM2.5 concentration of 469 μg m-3 occurred in Beijing. Comparisons with observations show that the model reproduced the temporal variability in PM2.5 with the highest PM2.5 values on polluted days (defined as days in which observed PM2.5 is greater than 75 μg m-3), but predictions of sulfate, nitrate, and ammonium were too low on days with the highest observed concentrations. Observational data indicate that the sulfur/nitric oxidation rates are strongly correlated with relative humidity during periods of peak PM2.5; however, the model failed to reproduce the highest PM2.5 concentrations due to missing heterogeneous/aqueous reactions. As the parameterizations of those heterogeneous reactions are not well established yet, estimates of SO2-to-H2SO4 and NO2/NO3-to-HNO3 reaction rates that depend on relative humidity were applied which improved the simulation of sulfate, nitrate, and ammonium enhancement on polluted days in terms of both concentrations and partitioning among those species. Sensitivity simulations showed that the extremely high heterogeneous reaction rates and also higher emission rates than those reported in the emission inventory were likely important factors contributing to those peak PM2.5 concentrations.

Joubert syndrome: A model for untangling recessive disorders with extreme genetic heterogeneity

PubMed Central

R, Bachmann-Gagescu; JC, Dempsey; IG, Phelps; BJ, O’Roak; DM, Knutzen; TC, Rue; GE, Ishak; CR, Isabella; N, Gorden; J, Adkins; EA, Boyle; N, de Lacy; D, O’Day; A, Alswaid; AR, Devi; L, Lingappa; C, Lourenço; L, Martorell; À, Garcia-Cazorla; H, Ozyürek; G, Haliloğlu; B, Tuysuz; M, Topçu; P, Chance; MA, Parisi; I, Glass; J, Shendure; D, Doherty

2016-01-01

Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion (CADD) algorithm with an optimized score cut-off. Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a “pure JS” phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS-subtypes. Conclusion This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes, and enable gene-specific treatments in the future. PMID:26092869

Extreme Threshold Failures Within a Heterogeneous Elastic Thin Sheet and the Spatial-Temporal Development of Induced Seismicity Within the Groningen Gas Field

NASA Astrophysics Data System (ADS)

Bourne, S. J.; Oates, S. J.

2017-12-01

Measurements of the strains and earthquakes induced by fluid extraction from a subsurface reservoir reveal a transient, exponential-like increase in seismicity relative to the volume of fluids extracted. If the frictional strength of these reactivating faults is heterogeneously and randomly distributed, then progressive failures of the weakest fault patches account in a general manner for this initial exponential-like trend. Allowing for the observable elastic and geometric heterogeneity of the reservoir, the spatiotemporal evolution of induced seismicity over 5 years is predictable without significant bias using a statistical physics model of poroelastic reservoir deformations inducing extreme threshold frictional failures of previously inactive faults. This model is used to forecast the temporal and spatial probability density of earthquakes within the Groningen natural gas reservoir, conditional on future gas production plans. Probabilistic seismic hazard and risk assessments based on these forecasts inform the current gas production policy and building strengthening plans.

Pointwise mutual information quantifies intratumor heterogeneity in tissue sections labeled with multiple fluorescent biomarkers

PubMed Central

Spagnolo, Daniel M.; Gyanchandani, Rekha; Al-Kofahi, Yousef; Stern, Andrew M.; Lezon, Timothy R.; Gough, Albert; Meyer, Dan E.; Ginty, Fiona; Sarachan, Brion; Fine, Jeffrey; Lee, Adrian V.; Taylor, D. Lansing; Chennubhotla, S. Chakra

2016-01-01

Background: Measures of spatial intratumor heterogeneity are potentially important diagnostic biomarkers for cancer progression, proliferation, and response to therapy. Spatial relationships among cells including cancer and stromal cells in the tumor microenvironment (TME) are key contributors to heterogeneity. Methods: We demonstrate how to quantify spatial heterogeneity from immunofluorescence pathology samples, using a set of 3 basic breast cancer biomarkers as a test case. We learn a set of dominant biomarker intensity patterns and map the spatial distribution of the biomarker patterns with a network. We then describe the pairwise association statistics for each pattern within the network using pointwise mutual information (PMI) and visually represent heterogeneity with a two-dimensional map. Results: We found a salient set of 8 biomarker patterns to describe cellular phenotypes from a tissue microarray cohort containing 4 different breast cancer subtypes. After computing PMI for each pair of biomarker patterns in each patient and tumor replicate, we visualize the interactions that contribute to the resulting association statistics. Then, we demonstrate the potential for using PMI as a diagnostic biomarker, by comparing PMI maps and heterogeneity scores from patients across the 4 different cancer subtypes. Estrogen receptor positive invasive lobular carcinoma patient, AL13-6, exhibited the highest heterogeneity score among those tested, while estrogen receptor negative invasive ductal carcinoma patient, AL13-14, exhibited the lowest heterogeneity score. Conclusions: This paper presents an approach for describing intratumor heterogeneity, in a quantitative fashion (via PMI), which departs from the purely qualitative approaches currently used in the clinic. PMI is generalizable to highly multiplexed/hyperplexed immunofluorescence images, as well as spatial data from complementary in situ methods including FISSEQ and CyTOF, sampling many different components within the TME. We hypothesize that PMI will uncover key spatial interactions in the TME that contribute to disease proliferation and progression. PMID:27994939

Soil variability along a nitrogen mineralization and nitrification gradient in a nitrogen-saturated hardwood forest

Treesearch

Frank S. Gilliam; Nikki L. Lyttle; Ashley Thomas; Mary Beth Adams

2005-01-01

Some N-saturated watersheds of the Fernow Experimental Forest (FEF), West Virginia, exhibit a high degree of spatial heterogeneity in soil N processing. We used soils from four sites at FEF representing a gradient in net N mineralization and nitrification to consider the causes and consequences of such spatial heterogeneity. We collected soils with extremely high vs....

Thinning of heterogeneous lithosphere: insights from field observations and numerical modelling

NASA Astrophysics Data System (ADS)

Petri, B.; Duretz, T.; Mohn, G.; Schmalholz, S. M.

2017-12-01

The nature and mechanisms of formation of extremely thinned continental crust (< 10 km) and lithosphere during rifting remain debated. Observations from present-day and fossil continental passive margins document the heterogeneous nature of the lithosphere characterized, among others, by lithological variations and structural inheritance. This contribution aims at investigating the mechanisms of extreme lithospheric thinning by exploring in particular the role of initial heterogeneities by coupling field observations from fossil passive margins and numerical models of lithospheric extension. Two field examples from the Alpine Tethys margins outcropping in the Eastern Alps (E Switzerland and N Italy) and in the Southern Alps (N Italy) were selected for their exceptional level of preservation of rift-related structures. This situation enables us to characterize (1) the pre-rift architecture of the continental lithosphere, (2) the localization of rift-related deformation in distinct portion of the lithosphere and (3) the interaction between initial heterogeneities of the lithosphere and rift-related structures. In a second stage, these observations are integrated in high-resolution, two-dimensional thermo-mechanical models taking into account various patterns of initial mechanical heterogeneities. Our results show the importance of initial pre-rift architecture of the continental lithosphere during rifting. Key roles are given to high-angle and low-angle normal faults, anastomosing shear-zones and decoupling horizons. We propose that during the first stages of thinning, deformation is strongly controlled by the complex pre-rift architecture of the lithosphere, localized along major structures responsible for the lateral extrusion of mid to lower crustal levels. This extrusion juxtaposes mechanically stronger levels in the hyper-thinned continental crust, being exhumed by subsequent low-angle normal faults. Altogether, these results highlight the critical role of the extraction of mechanically strong layers of the lithosphere during the extreme thinning of the continental lithosphere and allows to propose a new model for the formation of continental passive margins.

High-z X-ray Obscured Quasars in Galaxies with Extreme Mid-IR/Optical Colors

NASA Astrophysics Data System (ADS)

Piconcelli, E.; Lanzuisi, G.; Fiore, F.; Feruglio, C.; Vignali, C.; Salvato, M.; Grappioni, C.

2009-05-01

Extreme Optical/Mid-IR color cuts have been used to uncover a population of dust-enshrouded, mid-IR luminous galaxies at high redshifts. Several lines of evidence point towards the presence of an heavily absorbed, possibly Compton-thick quasar at the heart of these systems. Nonetheless, the X-ray spectral properties of these intriguing sources still remain largely unexplored. Here we present an X-ray spectroscopic study of a large sample of 44 extreme dust-obscured galaxies (EDOGs) with F24 μm/FR>2000 and F24 μm>1.3 mJy selected from a 6 deg2 region in the SWIRE fields. The application of our selection criteria to a wide area survey has been capable of unveiling a population of X-ray luminous, absorbed z>1 quasars which is mostly missed in the traditional optical/X-ray surveys performed so far. Advances in the understanding of the X-ray properties of these recently-discovered sources by Simbol-X observations will be also discussed.

Uncovering Clinical Features of De Novo Philadelphia Positive Myelodysplasia.

PubMed

Armas, Aristides; Chen, Chen; Mims, Martha; Rivero, Gustavo

2017-01-01

Myelodysplastic syndrome (MDS) is cytogenetically heterogeneous and retains variable risk for acute myeloid leukemia transformation. Though not yet fully understood, there is an association between genetic abnormalities and defects in gene expression. The functional role for infrequent cytogenetic alteration remains unclear. An uncommon chromosomic abnormality is the presence of the Philadelphia (Ph) chromosome. Here, we report a patient with Ph+ MDS treated with low dose Dasatinib who achieved hematologic response for 7 months. In addition, we also examined the English literature on all de novo Ph + MDS cases between 1996 and 2015 to gain insight into clinical features and outcome.

Uncovering Clinical Features of De Novo Philadelphia Positive Myelodysplasia

PubMed Central

Armas, Aristides; Chen, Chen; Mims, Martha

2017-01-01

Myelodysplastic syndrome (MDS) is cytogenetically heterogeneous and retains variable risk for acute myeloid leukemia transformation. Though not yet fully understood, there is an association between genetic abnormalities and defects in gene expression. The functional role for infrequent cytogenetic alteration remains unclear. An uncommon chromosomic abnormality is the presence of the Philadelphia (Ph) chromosome. Here, we report a patient with Ph+ MDS treated with low dose Dasatinib who achieved hematologic response for 7 months. In addition, we also examined the English literature on all de novo Ph + MDS cases between 1996 and 2015 to gain insight into clinical features and outcome. PMID:28321349

Characterizing heterogeneous cellular responses to perturbations.

PubMed

Slack, Michael D; Martinez, Elisabeth D; Wu, Lani F; Altschuler, Steven J

2008-12-09

Cellular populations have been widely observed to respond heterogeneously to perturbation. However, interpreting the observed heterogeneity is an extremely challenging problem because of the complexity of possible cellular phenotypes, the large dimension of potential perturbations, and the lack of methods for separating meaningful biological information from noise. Here, we develop an image-based approach to characterize cellular phenotypes based on patterns of signaling marker colocalization. Heterogeneous cellular populations are characterized as mixtures of phenotypically distinct subpopulations, and responses to perturbations are summarized succinctly as probabilistic redistributions of these mixtures. We apply our method to characterize the heterogeneous responses of cancer cells to a panel of drugs. We find that cells treated with drugs of (dis-)similar mechanism exhibit (dis-)similar patterns of heterogeneity. Despite the observed phenotypic diversity of cells observed within our data, low-complexity models of heterogeneity were sufficient to distinguish most classes of drug mechanism. Our approach offers a computational framework for assessing the complexity of cellular heterogeneity, investigating the degree to which perturbations induce redistributions of a limited, but nontrivial, repertoire of underlying states and revealing functional significance contained within distinct patterns of heterogeneous responses.

Uncovering a New Moral Dilemma of Economic Optimization in Biotechnological Processing.

PubMed

Vochozka, Marek; Stehel, Vojtěch; Maroušková, Anna

2017-06-08

The trend of emerging biorefineries is to process the harvest as efficiently as possible and without any waste. From the most valuable phytomass, refined medicines, enzymes, dyes and other special reactants are created. Functional foods, food ingredients, oils, alcohol, solvents, plastics, fillers and a wide variety of other chemical products follow. After being treated with nutrient recovery techniques (for fertilizer production), biofuels or soil improvers are produced from the leftovers. Economic optimization algorithms have confirmed that such complex biorefineries can be financially viable only when a high degree of feedstock concentration is included. Because the plant material is extremely voluminous before processing, the farming intensity of special plants increases in the nearest vicinity of agglomerations where the biorefineries are built for logistical reasons. Interdisciplinary analyses revealed that these optimization measures lead to significantly increased pollen levels in neighbouring urban areas and subsequently an increased risk of allergies, respectively costs to the national health system. A new moral dilemma between the shareholder's profit and public interest was uncovered and subjected to disputation.

FGFR4 signaling couples to Bim and not Bmf to discriminate subsets of alveolar rhabdomyosarcoma cells.

PubMed

Wachtel, Marco; Rakic, Jelena; Okoniewski, Michal; Bode, Peter; Niggli, Felix; Schäfer, Beat W

2014-10-01

Biological heterogeneity represents a major obstacle for cancer treatment. Therefore, characterization of treatment-relevant tumor heterogeneity is necessary to develop more effective therapies in the future. Here, we uncovered population heterogeneity among PAX/FOXO1-positive alveolar rhabdomyosarcoma by characterizing prosurvival networks initiated by FGFR4 signaling. We found that FGFR4 signaling rescues only subgroups of alveolar rhabdomyosarcoma cells from apoptosis induced by compounds targeting the IGF1R-PI3K-mTOR pathway. Differences in both proapoptotic machinery and FGFR4-activated signaling are involved in the different behavior of the phenotypes. Proapoptotic stress induced by the kinase inhibitors is sensed by Bim/Bad in rescue cells and by Bmf in nonrescue cells. Anti-apoptotic ERK1/2 signaling downstream of FGFR4 is long-lasting in rescue and short-termed in most non-rescue cells. Gene expression analysis detected signatures specific for these two groups also in biopsy samples. The different cell phenotypes are present in different ratios in alveolar rhabdomyosarcoma tumors and can be identified by AP2β expression levels. Hence, inhibiting FGFR signaling might represent an important strategy to enhance efficacy of current RMS treatments. © 2014 UICC.

Why Do Some People Do “More” to Mitigate Climate Change than Others? Exploring Heterogeneity in Psycho-Social Associations

PubMed Central

Ortega-Egea, José Manuel; García-de-Frutos, Nieves; Antolín-López, Raquel

2014-01-01

The urgency of climate change mitigation calls for a profound shift in personal behavior. This paper investigates psycho-social correlates of extra mitigation behavior in response to climate change, while also testing for potential (unobserved) heterogeneity in European citizens' decision-making. A person's extra mitigation behavior in response to climate change is conceptualized—and differentiated from common mitigation behavior—as some people's broader and greater levels of behavioral engagement (compared to others) across specific self-reported mitigation actions and behavioral domains. Regression analyses highlight the importance of environmental psychographics (i.e., attitudes, motivations, and knowledge about climate change) and socio-demographics (especially country-level variables) in understanding extra mitigation behavior. By looking at the data through the lens of segmentation, significant heterogeneity is uncovered in the associations of attitudes and knowledge about climate change—but not in motivational or socio-demographic links—with extra mitigation behavior in response to climate change, across two groups of environmentally active respondents. The study has implications for promoting more ambitious behavioral responses to climate change, both at the individual level and across countries. PMID:25191841

Patterns of precipitation and soil moisture extremes in Texas, US: A complex network analysis

NASA Astrophysics Data System (ADS)

Sun, Alexander Y.; Xia, Youlong; Caldwell, Todd G.; Hao, Zengchao

2018-02-01

Understanding of the spatial and temporal dynamics of extreme precipitation not only improves prediction skills, but also helps to prioritize hazard mitigation efforts. This study seeks to enhance the understanding of spatiotemporal covariation patterns embedded in precipitation (P) and soil moisture (SM) by using an event-based, complex-network-theoretic approach. Events concurrences are quantified using a nonparametric event synchronization measure, and spatial patterns of hydroclimate variables are analyzed by using several network measures and a community detection algorithm. SM-P coupling is examined using a directional event coincidence analysis measure that takes the order of event occurrences into account. The complex network approach is demonstrated for Texas, US, a region possessing a rich set of hydroclimate features and is frequented by catastrophic flooding. Gridded daily observed P data and simulated SM data are used to create complex networks of P and SM extremes. The uncovered high degree centrality regions and community structures are qualitatively in agreement with the overall existing knowledge of hydroclimate extremes in the study region. Our analyses provide new visual insights on the propagation, connectivity, and synchronicity of P extremes, as well as the SM-P coupling, in this flood-prone region, and can be readily used as a basis for event-driven predictive analytics for other regions.

Numerical modeling of macrodispersion in heterogeneous media: a comparison of multi-Gaussian and non-multi-Gaussian models

NASA Astrophysics Data System (ADS)

Wen, Xian-Huan; Gómez-Hernández, J. Jaime

1998-03-01

The macrodispersion of an inert solute in a 2-D heterogeneous porous media is estimated numerically in a series of fields of varying heterogeneity. Four different random function (RF) models are used to model log-transmissivity (ln T) spatial variability, and for each of these models, ln T variance is varied from 0.1 to 2.0. The four RF models share the same univariate Gaussian histogram and the same isotropic covariance, but differ from one another in terms of the spatial connectivity patterns at extreme transmissivity values. More specifically, model A is a multivariate Gaussian model for which, by definition, extreme values (both high and low) are spatially uncorrelated. The other three models are non-multi-Gaussian: model B with high connectivity of high extreme values, model C with high connectivity of low extreme values, and model D with high connectivities of both high and low extreme values. Residence time distributions (RTDs) and macrodispersivities (longitudinal and transverse) are computed on ln T fields corresponding to the different RF models, for two different flow directions and at several scales. They are compared with each other, as well as with predicted values based on first-order analytical results. Numerically derived RTDs and macrodispersivities for the multi-Gaussian model are in good agreement with analytically derived values using first-order theories for log-transmissivity variance up to 2.0. The results from the non-multi-Gaussian models differ from each other and deviate largely from the multi-Gaussian results even when ln T variance is small. RTDs in non-multi-Gaussian realizations with high connectivity at high extreme values display earlier breakthrough than in multi-Gaussian realizations, whereas later breakthrough and longer tails are observed for RTDs from non-multi-Gaussian realizations with high connectivity at low extreme values. Longitudinal macrodispersivities in the non-multi-Gaussian realizations are, in general, larger than in the multi-Gaussian ones, while transverse macrodispersivities in the non-multi-Gaussian realizations can be larger or smaller than in the multi-Gaussian ones depending on the type of connectivity at extreme values. Comparing the numerical results for different flow directions, it is confirmed that macrodispersivities in multi-Gaussian realizations with isotropic spatial correlation are not flow direction-dependent. Macrodispersivities in the non-multi-Gaussian realizations, however, are flow direction-dependent although the covariance of ln T is isotropic (the same for all four models). It is important to account for high connectivities at extreme transmissivity values, a likely situation in some geological formations. Some of the discrepancies between first-order-based analytical results and field-scale tracer test data may be due to the existence of highly connected paths of extreme conductivity values.

The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome.

PubMed

Caswell, Deborah R; Swanton, Charles

2017-07-18

The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes. Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a major cause of resistance to therapy and relapse. Heterogeneity may fuel metastasis through the selection of rare, aggressive, somatically altered cells. However, extreme levels of chromosomal instability, which contribute to intratumour heterogeneity, are associated with improved patient outcomes, suggesting a delicate balance between high and low levels of genome instability. We review evidence that intratumour heterogeneity influences tumour evolution, including metastasis, drug resistance, and the immune response. We discuss the prevalence of tumour heterogeneity, and how it can be initiated and sustained by external and internal forces. Understanding tumour evolution and metastasis could yield novel therapies that leverage the immune system to control emerging tumour neo-antigens.

XDGMM: eXtreme Deconvolution Gaussian Mixture Modeling

NASA Astrophysics Data System (ADS)

Holoien, Thomas W.-S.; Marshall, Philip J.; Wechsler, Risa H.

2017-08-01

XDGMM uses Gaussian mixtures to do density estimation of noisy, heterogenous, and incomplete data using extreme deconvolution (XD) algorithms which is compatible with the scikit-learn machine learning methods. It implements both the astroML and Bovy et al. (2011) algorithms, and extends the BaseEstimator class from scikit-learn so that cross-validation methods work. It allows the user to produce a conditioned model if values of some parameters are known.

Microstructure-Sensitive Extreme Value Probabilities for High Cycle Fatigue of Ni-Base Superalloy IN100 (Preprint)

DTIC Science & Technology

2009-03-01

transition fatigue regimes; however, microplasticity (i.e., heterogeneous plasticity at the scale of microstructure) is relevant to understanding fatigue...and Socie [57] considered the affect of microplastic 14 Microstructure-Sensitive Extreme Value Probabilities for High Cycle Fatigue of Ni-Base...considers the local stress state as affected by intergranular interactions and microplasticity . For the calculations given below, the volumes over which

Molecular Signatures of Tissue-Specific Microvascular Endothelial Cell Heterogeneity in Organ Maintenance and Regeneration

PubMed Central

Nolan, Daniel J.; Ginsberg, Michael; Israely, Edo; Palikuqi, Brisa; Poulos, Michael G.; James, Daylon; Ding, Bi-Sen; Schachterle, William; Liu, Ying; Rosenwaks, Zev; Butler, Jason M.; Xiang, Jenny; Rafii, Arash; Shido, Koji; Rabbany, Sina Y.; Elemento, Olivier; Rafii, Shahin

2013-01-01

SUMMARY Microvascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. These libraries identify attributes that confer ECs with their organotypic features. We show that clusters of transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by ECs of each organ. Furthermore, ECs respond distinctly in tissue regeneration models, hepatectomy, and myeloablation. To test the data set, we developed a transplantation model that employs generic ECs differentiated from embryonic stem cells. Transplanted generic ECs engraft into regenerating tissues and acquire features of organotypic ECs. Collectively, we demonstrate the utility of informational databases of ECs toward uncovering the extravascular and intrinsic signals that define EC heterogeneity. These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration. PMID:23871589

CRISPR-UMI: single-cell lineage tracing of pooled CRISPR-Cas9 screens.

PubMed

Michlits, Georg; Hubmann, Maria; Wu, Szu-Hsien; Vainorius, Gintautas; Budusan, Elena; Zhuk, Sergei; Burkard, Thomas R; Novatchkova, Maria; Aichinger, Martin; Lu, Yiqing; Reece-Hoyes, John; Nitsch, Roberto; Schramek, Daniel; Hoepfner, Dominic; Elling, Ulrich

2017-12-01

Pooled CRISPR screens are a powerful tool for assessments of gene function. However, conventional analysis is based exclusively on the relative abundance of integrated single guide RNAs (sgRNAs) between populations, which does not discern distinct phenotypes and editing outcomes generated by identical sgRNAs. Here we present CRISPR-UMI, a single-cell lineage-tracing methodology for pooled screening to account for cell heterogeneity. We generated complex sgRNA libraries with unique molecular identifiers (UMIs) that allowed for screening of clonally expanded, individually tagged cells. A proof-of-principle CRISPR-UMI negative-selection screen provided increased sensitivity and robustness compared with conventional analysis by accounting for underlying cellular and editing-outcome heterogeneity and detection of outlier clones. Furthermore, a CRISPR-UMI positive-selection screen uncovered new roadblocks in reprogramming mouse embryonic fibroblasts as pluripotent stem cells, distinguishing reprogramming frequency and speed (i.e., effect size and probability). CRISPR-UMI boosts the predictive power, sensitivity, and information content of pooled CRISPR screens.

Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia

PubMed Central

Wang, Lili; Fan, Jean; Francis, Joshua M.; Georghiou, George; Hergert, Sarah; Li, Shuqiang; Gambe, Rutendo; Zhou, Chensheng W.; Yang, Chunxiao; Xiao, Sheng; Cin, Paola Dal; Bowden, Michaela; Kotliar, Dylan; Shukla, Sachet A.; Brown, Jennifer R.; Neuberg, Donna; Alessi, Dario R.; Zhang, Cheng-Zhong; Kharchenko, Peter V.; Livak, Kenneth J.; Wu, Catherine J.

2017-01-01

Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype–phenotype relationships, we developed methods for targeted mutation detection in DNA and RNA isolated from thousands of single cells from five CLL samples. By clearly resolving phylogenic relationships, we uncovered mutated LCP1 and WNK1 as novel CLL drivers, supported by functional evidence demonstrating their impact on CLL pathways. Integrative analysis of somatic mutations with transcriptional states prompts the idea that convergent evolution generates phenotypically similar cells in distinct genetic branches, thus creating a cohesive expression profile in each CLL sample despite the presence of genetic heterogeneity. Our study highlights the potential for single-cell RNA-based targeted analysis to sensitively determine transcriptional and mutational profiles of individual cancer cells, leading to increased understanding of driving events in malignancy. PMID:28679620

Cognitive impairment categorized in community-dwelling older adults with and without dementia using in-home sensors that recognise activities of daily living

NASA Astrophysics Data System (ADS)

Urwyler, Prabitha; Stucki, Reto; Rampa, Luca; Müri, René; Mosimann, Urs P.; Nef, Tobias

2017-02-01

Cognitive impairment due to dementia decreases functionality in Activities of Daily Living (ADL). Its assessment is useful to identify care needs, risks and monitor disease progression. This study investigates differences in ADL pattern-performance between dementia patients and healthy controls using unobtrusive sensors. Around 9,600 person-hours of activity data were collected from the home of ten dementia patients and ten healthy controls using a wireless-unobtrusive sensors and analysed to detect ADL. Recognised ADL were visualized using activity maps, the heterogeneity and accuracy to discriminate patients from healthy were analysed. Activity maps of dementia patients reveal unorganised behaviour patterns and heterogeneity differed significantly between the healthy and diseased. The discriminating accuracy increases with observation duration (0.95 for 20 days). Unobtrusive sensors quantify ADL-relevant behaviour, useful to uncover the effect of cognitive impairment, to quantify ADL-relevant changes in the course of dementia and to measure outcomes of anti-dementia treatments.

Metagenomic Analysis of Hot Springs in Central India Reveals Hydrocarbon Degrading Thermophiles and Pathways Essential for Survival in Extreme Environments.

PubMed

Saxena, Rituja; Dhakan, Darshan B; Mittal, Parul; Waiker, Prashant; Chowdhury, Anirban; Ghatak, Arundhuti; Sharma, Vineet K

2016-01-01

Extreme ecosystems such as hot springs are of great interest as a source of novel extremophilic species, enzymes, metabolic functions for survival and biotechnological products. India harbors hundreds of hot springs, the majority of which are not yet explored and require comprehensive studies to unravel their unknown and untapped phylogenetic and functional diversity. The aim of this study was to perform a large-scale metagenomic analysis of three major hot springs located in central India namely, Badi Anhoni, Chhoti Anhoni, and Tattapani at two geographically distinct regions (Anhoni and Tattapani), to uncover the resident microbial community and their metabolic traits. Samples were collected from seven distinct sites of the three hot spring locations with temperature ranging from 43.5 to 98°C. The 16S rRNA gene amplicon sequencing of V3 hypervariable region and shotgun metagenome sequencing uncovered a unique taxonomic and metabolic diversity of the resident thermophilic microbial community in these hot springs. Genes associated with hydrocarbon degradation pathways, such as benzoate, xylene, toluene, and benzene were observed to be abundant in the Anhoni hot springs (43.5-55°C), dominated by Pseudomonas stutzeri and Acidovorax sp., suggesting the presence of chemoorganotrophic thermophilic community with the ability to utilize complex hydrocarbons as a source of energy. A high abundance of genes belonging to methane metabolism pathway was observed at Chhoti Anhoni hot spring, where methane is reported to constitute >80% of all the emitted gases, which was marked by the high abundance of Methylococcus capsulatus . The Tattapani hot spring, with a high-temperature range (61.5-98°C), displayed a lower microbial diversity and was primarily dominated by a nitrate-reducing archaeal species Pyrobaculum aerophilum . A higher abundance of cell metabolism pathways essential for the microbial survival in extreme conditions was observed at Tattapani. Taken together, the results of this study reveal a novel consortium of microbes, genes, and pathways associated with the hot spring environment.

Integrated approaches to long-term studies of urban ecological systems

Treesearch

Nancy B. Grimm; J. Morgan Grove; Steward T.A. Pickett; Charles L. Redman

2000-01-01

Urban ecological systems present multiple challenges to ecologists—pervasive human impact and extreme heterogeneity of cities, and the need to integrate social and ecological approaches, concepts, and theory.

Mirror therapy for motor function of the upper extremity in patients with stroke: A meta-analysis.

PubMed

Zeng, Wen; Guo, Yonghong; Wu, Guofeng; Liu, Xueyan; Fang, Qian

2018-01-10

To evaluate the mean treatment effect of mirror therapy on motor function of the upper extremity in patients with stroke. Electronic databases, including the Cochrane Library, PubMed, MEDLINE, Embase and CNKSystematic, were searched for relevant studies published in English between 1 January 2007 and 22 June 2017. Randomized controlled trials and pilot randomized controlled trials that compared mirror therapy/mirror box therapy with other rehabilitation approaches were selected. Two authors independently evaluated the searched studies based on the inclusion/exclusion criteria and appraised the quality of included studies according to the criteria of the updated version 5.1.0 of the Cochrane Handbook for Systematic Review of Interventions. Eleven trials, with a total of 347 patients, were included in the meta-analysis. A moderate effect of mirror therapy (standardized mean difference 0.51, 95% confidence interval (CI) 0.29, 0.73) on motor function of the upper extremity was found. However, a high degree of heterogeneity (χ2 = 25.65, p = 0.004; I2 = 61%) was observed. The heterogeneity decreased a great deal (χ2 = 6.26, p = 0.62; I2 = 0%) after 2 trials were excluded though sensitivity analysis. Although the included studies had high heterogeneity, meta-analysis provided some evidence that mirror therapy may significantly improve motor function of the upper limb in patients with stroke. Further well-designed studies are needed.

Pattern Analysis of Dynamic Susceptibility Contrast-enhanced MR Imaging Demonstrates Peritumoral Tissue Heterogeneity

PubMed Central

Akbari, Hamed; Macyszyn, Luke; Da, Xiao; Wolf, Ronald L.; Bilello, Michel; Verma, Ragini; O’Rourke, Donald M.

2014-01-01

Purpose To augment the analysis of dynamic susceptibility contrast material–enhanced magnetic resonance (MR) images to uncover unique tissue characteristics that could potentially facilitate treatment planning through a better understanding of the peritumoral region in patients with glioblastoma. Materials and Methods Institutional review board approval was obtained for this study, with waiver of informed consent for retrospective review of medical records. Dynamic susceptibility contrast-enhanced MR imaging data were obtained for 79 patients, and principal component analysis was applied to the perfusion signal intensity. The first six principal components were sufficient to characterize more than 99% of variance in the temporal dynamics of blood perfusion in all regions of interest. The principal components were subsequently used in conjunction with a support vector machine classifier to create a map of heterogeneity within the peritumoral region, and the variance of this map served as the heterogeneity score. Results The calculated principal components allowed near-perfect separability of tissue that was likely highly infiltrated with tumor and tissue that was unlikely infiltrated with tumor. The heterogeneity map created by using the principal components showed a clear relationship between voxels judged by the support vector machine to be highly infiltrated and subsequent recurrence. The results demonstrated a significant correlation (r = 0.46, P < .0001) between the heterogeneity score and patient survival. The hazard ratio was 2.23 (95% confidence interval: 1.4, 3.6; P < .01) between patients with high and low heterogeneity scores on the basis of the median heterogeneity score. Conclusion Analysis of dynamic susceptibility contrast-enhanced MR imaging data by using principal component analysis can help identify imaging variables that can be subsequently used to evaluate the peritumoral region in glioblastoma. These variables are potentially indicative of tumor infiltration and may become useful tools in guiding therapy, as well as individualized prognostication. © RSNA, 2014 PMID:24955928

Playing the Fertility Game at Work: An Equilibrium Model of Peer Effects.

PubMed

Ciliberto, Federico; Miller, Amalia R; Nielsen, Helena Skyt; Simonsen, Marianne

2016-08-01

We study workplace peer effects in fertility decisions using a game theory model of strategic interactions among coworkers that allows for multiple equilibria. Using register-based data on fertile-aged women working in medium sized establishments in Denmark, we uncover negative average peer effects. Allowing for heterogeneous effects by worker type, we find that positive effects dominate across worker types defined by age or education. Negative effects dominate within age groups and among low-education types. Policy simulations show that these estimated effects make the distribution of where women work an important consideration, beyond simply if they work, in predicting population fertility.

Playing the Fertility Game at Work: An Equilibrium Model of Peer Effects

PubMed Central

Ciliberto, Federico; Miller, Amalia R.; Nielsen, Helena Skyt; Simonsen, Marianne

2016-01-01

We study workplace peer effects in fertility decisions using a game theory model of strategic interactions among coworkers that allows for multiple equilibria. Using register-based data on fertile-aged women working in medium sized establishments in Denmark, we uncover negative average peer effects. Allowing for heterogeneous effects by worker type, we find that positive effects dominate across worker types defined by age or education. Negative effects dominate within age groups and among low-education types. Policy simulations show that these estimated effects make the distribution of where women work an important consideration, beyond simply if they work, in predicting population fertility. PMID:27605729

Drug targeting of oncogenic pathways in melanoma.

PubMed

Fecher, Leslie A; Amaravadi, Ravi K; Schuchter, Lynn M; Flaherty, Keith T

2009-06-01

Melanoma continues to be one of the most aggressive and morbid malignancies once metastatic. Overall survival for advanced unresectable melanoma has not changed over the past several decades. However, the presence of some long-term survivors of metastatic melanoma highlights the heterogeneity of this disease and the potential for improved outcomes. Current research is uncovering the molecular and genetic scaffolding of normal and aberrant cell function. The known oncogenic pathways in melanoma and the attempts to develop therapy for them are discussed. The targeting of certain cellular processes, downstream of the common genetic alterations, for which the issues of target and drug validation are somewhat distinct, are also highlighted.

Pluridirectional High-Energy Agile Scanning Electron Radiotherapy (PHASER): Extremely Rapid Treatment for Early Lung Cancer

DTIC Science & Technology

2014-06-01

BEAMnrc Monte Carlo (MC) codes were used to simulate 50- 150MeV VHEE beam dose deposition and its effects on steel and titanium (Ti) heterogeneities in a...performed on water-only geometry and water with segmented prostheses ( steel and Ti) geometries with 100MeV and 150MeV beams...8 Results: 100MeV PDD 5cm behind steel /Ti heterogeneity was 51% less than in the

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response. | Center for Cancer Research

Cancer.gov

Biswas et al. describe an “exceptional responder” lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for 7 years while undergoing single or combination ERBB2-directed therapies. Whole-genome, whole-exome, and high-coverage ion-torrent targeted sequencing were used to demonstrate extreme genomic heterogeneity between the lung and lymph node metastatic

Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned

PubMed Central

Gudi, Viktoria; Gingele, Stefan; Skripuletz, Thomas; Stangel, Martin

2014-01-01

Although astrogliosis and microglia activation are characteristic features of multiple sclerosis (MS) and other central nervous system (CNS) lesions the exact functions of these events are not fully understood. Animal models help to understand the complex interplay between the different cell types of the CNS and uncover general mechanisms of damage and repair of myelin sheaths. The so called cuprizone model is a toxic model of demyelination in the CNS white and gray matter, which lacks an autoimmune component. Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions. Although not suitable to study autoimmune mediated demyelination, this model is extremely helpful to elucidate basic cellular and molecular mechanisms during de- and particularly remyelination independently of interactions with peripheral immune cells. Phagocytosis and removal of damaged myelin seems to be one of the major roles of microglia in this model and it is well known that removal of myelin debris is a prerequisite of successful remyelination. Furthermore, microglia provide several signals that support remyelination. The role of astrocytes during de- and remyelination is not well defined. Both supportive and destructive functions have been suggested. Using the cuprizone model we could demonstrate that there is an important crosstalk between astrocytes and microglia. In this review we focus on the role of glial reactions and interaction in the cuprizone model. Advantages and limitations of as well as its potential therapeutic relevance for the human disease MS are critically discussed in comparison to other animal models. PMID:24659953

Heterogeneous conversion of CO2 into cyclic carbonates at ambient pressure catalyzed by ionothermal-derived meso-macroporous hierarchical poly(ionic liquid)s† †Electronic supplementary information (ESI) available: Experimental section, details of the IR, 13C NMR and XPS spectra, characterization (1H NMR, 13C NMR, 13C CP-MAS NMR, TG, XRD, SEM, elemental analysis), N2 adsorption–desorption isotherms, pore size distribution, recycling test of the catalyst, comparison of the literature catalytic activity of different heterogeneous catalysts. See DOI: 10.1039/c5sc02050f

PubMed Central

Wang, Xiaochen; Zhou, Yu; Guo, Zengjing; Chen, Guojian; Li, Jing; Shi, Yuming; Liu, Yangqing

2015-01-01

Meso-macroporous hierarchical poly(ionic liquid)s (MPILs) with extremely high ionic site densities and tunable pore structures were ionothermally synthesized through the free radical self-polymerization of our newly designed rigid bis-vinylimidazolium salt monomer. The synthesis avoided the use of any templates, gave a high yield (>99%) and allowed recycling of the IL solvent; thus it is facile, atom-efficient, environmentally friendly and sustainable. The synthesized MPILs possessed distinctive features of polycation matrices, abundant halogen anions, and large surface areas. They not only presented enhanced CO2 capture, but led to breakthroughs in the heterogeneous catalytic conversion of CO2 into cyclic carbonates: (1) unprecedented high activity at atmospheric pressure and low temperature; (2) good substrate compatibility, even being active towards the extremely inert aliphatic long carbon-chain alkyl epoxides. This result renders the first occasion of a metal–solvent–additive free recyclable heterogeneous cycloaddition of CO2 at such mild conditions. PMID:29861930

Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait.

PubMed

Gu, S M; Orth, U; Zankl, M; Schröder, J; Gal, A

1997-08-22

Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait.

Parallaxes for the Coldest Brown Dwarfs

NASA Astrophysics Data System (ADS)

Dupuy, Trent; Kraus, Adam; Liu, Michael

2014-12-01

Understanding extremely cool atmospheres is a major goal of both brown dwarf and exoplanet studies. The WISE all-sky survey has uncovered the coolest brown dwarfs to date including the first unambiguous Y dwarfs. These discoveries are spectroscopically estimated to have temperatures of ~300-500 K and masses of ~5-20 Mjup, overlapping discoveries from radial velocity exoplanet surveys. However, direct distances are needed to determine model-independent temperatures and to test the observed properties against theoretical models in this new physical frontier. From our Cycle 8 program, we have successfully measured the first robust parallaxes for these extremely low-luminosity objects using Spitzer [3.6]-band astrometry, made possible with our improved distortion solution for IRAC. Our results, comprising less than half the currently known late-T/Y census, have uncovered a number of puzzles. Perhaps the most intriguing is the possibility that the observed near-IR spectral types and spectral energy distributions do not follow a simple correspondence with temperature, in contrast to all other (hotter) substellar and stellar objects. We propose here to obtain definitive parallaxes and temperatures to the ~2 dozen known coldest brown dwarfs. For our Cycle 8 sample, these new data will double the time baseline, leading to major improvements over our preliminary results. We will also double the total sample with parallaxes for more recent discoveries. Altogether, our work will establish the temperature scale as a function of spectral type, delineate the cooling (and intrinsic scatter) through the T/Y transition, and enable strong test of theoretical models for these coldest brown dwarfs, which are ~100x fainter than previously known objects at near-IR wavelengths.

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms

PubMed Central

Monsma, David J; Cherba, David M; Eugster, Emily E; Dylewski, Dawna L; Davidson, Paula T; Peterson, Chelsea A; Borgman, Andrew S; Winn, Mary E; Dykema, Karl J; Webb, Craig P; MacKeigan, Jeffrey P; Duesbery, Nicholas S; Nickoloff, Brian J; Monks, Noel R

2015-01-01

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAFV600E models showed acquired drug resistance, one BRAFV600E model had a complete and durable response, and a BRAFV600V model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations. PMID:26101714

Quorum Sensing in Populations of Spatially Extended Chaotic Oscillators Coupled Indirectly via a Heterogeneous Environment

NASA Astrophysics Data System (ADS)

Li, Bing-Wei; Cao, Xiao-Zhi; Fu, Chenbo

2017-12-01

Many biological and chemical systems could be modeled by a population of oscillators coupled indirectly via a dynamical environment. Essentially, the environment by which the individual element communicates with each other is heterogeneous. Nevertheless, most of previous works considered the homogeneous case only. Here we investigated the dynamical behaviors in a population of spatially distributed chaotic oscillators immersed in a heterogeneous environment. Various dynamical synchronization states (such as oscillation death, phase synchronization, and complete synchronized oscillation) as well as their transitions were explored. In particular, we uncovered a non-traditional quorum sensing transition: increasing the population density leaded to a transition from oscillation death to synchronized oscillation at first, but further increasing the density resulted in degeneration from complete synchronization to phase synchronization or even from phase synchronization to desynchronization. The underlying mechanism of this finding was attributed to the dual roles played by the population density. What's more, by treating the environment as another component of the oscillator, the full system was then effectively equivalent to a locally coupled system. This fact allowed us to utilize the master stability functions approach to predict the occurrence of complete synchronization oscillation, which agreed with that from the direct numerical integration of the system. The potential candidates for the experimental realization of our model were also discussed.

Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing.

PubMed

Lalonde, Emilie; Albrecht, Steffen; Ha, Kevin C H; Jacob, Karine; Bolduc, Nathalie; Polychronakos, Constantin; Dechelotte, Pierre; Majewski, Jacek; Jabado, Nada

2010-08-01

Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., "whole exome") have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertions-deletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n=2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity.

Aberration hubs in protein interaction networks highlight actionable targets in cancer.

PubMed

Karimzadeh, Mehran; Jandaghi, Pouria; Papadakis, Andreas I; Trainor, Sebastian; Rung, Johan; Gonzàlez-Porta, Mar; Scelo, Ghislaine; Vasudev, Naveen S; Brazma, Alvis; Huang, Sidong; Banks, Rosamonde E; Lathrop, Mark; Najafabadi, Hamed S; Riazalhosseini, Yasser

2018-05-18

Despite efforts for extensive molecular characterization of cancer patients, such as the international cancer genome consortium (ICGC) and the cancer genome atlas (TCGA), the heterogeneous nature of cancer and our limited knowledge of the contextual function of proteins have complicated the identification of targetable genes. Here, we present Aberration Hub Analysis for Cancer (AbHAC) as a novel integrative approach to pinpoint aberration hubs, i.e. individual proteins that interact extensively with genes that show aberrant mutation or expression. Our analysis of the breast cancer data of the TCGA and the renal cancer data from the ICGC shows that aberration hubs are involved in relevant cancer pathways, including factors promoting cell cycle and DNA replication in basal-like breast tumors, and Src kinase and VEGF signaling in renal carcinoma. Moreover, our analysis uncovers novel functionally relevant and actionable targets, among which we have experimentally validated abnormal splicing of spleen tyrosine kinase as a key factor for cell proliferation in renal cancer. Thus, AbHAC provides an effective strategy to uncover novel disease factors that are only identifiable by examining mutational and expression data in the context of biological networks.

Summary of mutations underlying autosomal recessive congenital ichthyoses (ARCI) in Arabs with four novel mutations in ARCI-related genes from the United Arab Emirates.

PubMed

Bastaki, Fatma; Mohamed, Madiha; Nair, Pratibha; Saif, Fatima; Mustafa, Ethar M; Bizzari, Sami; Al-Ali, Mahmoud T; Hamzeh, Abdul Rezzak

2017-05-01

Clinical and molecular heterogeneity is a prominent characteristic of congenital ichthyoses, with the involvement of numerous causative loci. Mutations in these loci feature in autosomal recessive congenital ichthyoses (ARCIs) quite variably, with certain genes/mutations being more frequently uncovered in particular populations. In this study, we used whole exome sequencing as well as direct Sanger sequencing to uncover four novel mutations in ARCI-related genes, which were found in families from the United Arab Emirates. In silico tools such as CADD and SIFT Indel were used to predict the functional consequences of these mutations. The here-presented mutations occurred in three genes (ALOX12B, TGM1, ABCA12), and these are a mixture of missense and indel variants with damaging functional consequences on their encoded proteins. This study presents an overview of the mutations that were found in ARCI-related genes in Arabs and discusses molecular and clinical details pertaining to the above-mentioned Emirati cases and their novel mutations with special emphasis on the resulting protein changes. © 2017 The International Society of Dermatology.

Improving Classification Performance through an Advanced Ensemble Based Heterogeneous Extreme Learning Machines.

PubMed

Abuassba, Adnan O M; Zhang, Dezheng; Luo, Xiong; Shaheryar, Ahmad; Ali, Hazrat

2017-01-01

Extreme Learning Machine (ELM) is a fast-learning algorithm for a single-hidden layer feedforward neural network (SLFN). It often has good generalization performance. However, there are chances that it might overfit the training data due to having more hidden nodes than needed. To address the generalization performance, we use a heterogeneous ensemble approach. We propose an Advanced ELM Ensemble (AELME) for classification, which includes Regularized-ELM, L 2 -norm-optimized ELM (ELML2), and Kernel-ELM. The ensemble is constructed by training a randomly chosen ELM classifier on a subset of training data selected through random resampling. The proposed AELM-Ensemble is evolved by employing an objective function of increasing diversity and accuracy among the final ensemble. Finally, the class label of unseen data is predicted using majority vote approach. Splitting the training data into subsets and incorporation of heterogeneous ELM classifiers result in higher prediction accuracy, better generalization, and a lower number of base classifiers, as compared to other models (Adaboost, Bagging, Dynamic ELM ensemble, data splitting ELM ensemble, and ELM ensemble). The validity of AELME is confirmed through classification on several real-world benchmark datasets.

Improving Classification Performance through an Advanced Ensemble Based Heterogeneous Extreme Learning Machines

PubMed Central

Abuassba, Adnan O. M.; Ali, Hazrat

2017-01-01

Extreme Learning Machine (ELM) is a fast-learning algorithm for a single-hidden layer feedforward neural network (SLFN). It often has good generalization performance. However, there are chances that it might overfit the training data due to having more hidden nodes than needed. To address the generalization performance, we use a heterogeneous ensemble approach. We propose an Advanced ELM Ensemble (AELME) for classification, which includes Regularized-ELM, L2-norm-optimized ELM (ELML2), and Kernel-ELM. The ensemble is constructed by training a randomly chosen ELM classifier on a subset of training data selected through random resampling. The proposed AELM-Ensemble is evolved by employing an objective function of increasing diversity and accuracy among the final ensemble. Finally, the class label of unseen data is predicted using majority vote approach. Splitting the training data into subsets and incorporation of heterogeneous ELM classifiers result in higher prediction accuracy, better generalization, and a lower number of base classifiers, as compared to other models (Adaboost, Bagging, Dynamic ELM ensemble, data splitting ELM ensemble, and ELM ensemble). The validity of AELME is confirmed through classification on several real-world benchmark datasets. PMID:28546808

MaRIE theory, modeling and computation roadmap executive summary

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lookman, Turab

The confluence of MaRIE (Matter-Radiation Interactions in Extreme) and extreme (exascale) computing timelines offers a unique opportunity in co-designing the elements of materials discovery, with theory and high performance computing, itself co-designed by constrained optimization of hardware and software, and experiments. MaRIE's theory, modeling, and computation (TMC) roadmap efforts have paralleled 'MaRIE First Experiments' science activities in the areas of materials dynamics, irradiated materials and complex functional materials in extreme conditions. The documents that follow this executive summary describe in detail for each of these areas the current state of the art, the gaps that exist and the road mapmore » to MaRIE and beyond. Here we integrate the various elements to articulate an overarching theme related to the role and consequences of heterogeneities which manifest as competing states in a complex energy landscape. MaRIE experiments will locate, measure and follow the dynamical evolution of these heterogeneities. Our TMC vision spans the various pillar science and highlights the key theoretical and experimental challenges. We also present a theory, modeling and computation roadmap of the path to and beyond MaRIE in each of the science areas.« less

Do regional methods really help reduce uncertainties in flood frequency analyses?

NASA Astrophysics Data System (ADS)

Cong Nguyen, Chi; Payrastre, Olivier; Gaume, Eric

2013-04-01

Flood frequency analyses are often based on continuous measured series at gauge sites. However, the length of the available data sets is usually too short to provide reliable estimates of extreme design floods. To reduce the estimation uncertainties, the analyzed data sets have to be extended either in time, making use of historical and paleoflood data, or in space, merging data sets considered as statistically homogeneous to build large regional data samples. Nevertheless, the advantage of the regional analyses, the important increase of the size of the studied data sets, may be counterbalanced by the possible heterogeneities of the merged sets. The application and comparison of four different flood frequency analysis methods to two regions affected by flash floods in the south of France (Ardèche and Var) illustrates how this balance between the number of records and possible heterogeneities plays in real-world applications. The four tested methods are: (1) a local statistical analysis based on the existing series of measured discharges, (2) a local analysis valuating the existing information on historical floods, (3) a standard regional flood frequency analysis based on existing measured series at gauged sites and (4) a modified regional analysis including estimated extreme peak discharges at ungauged sites. Monte Carlo simulations are conducted to simulate a large number of discharge series with characteristics similar to the observed ones (type of statistical distributions, number of sites and records) to evaluate to which extent the results obtained on these case studies can be generalized. These two case studies indicate that even small statistical heterogeneities, which are not detected by the standard homogeneity tests implemented in regional flood frequency studies, may drastically limit the usefulness of such approaches. On the other hand, these result show that the valuation of information on extreme events, either historical flood events at gauged sites or estimated extremes at ungauged sites in the considered region, is an efficient way to reduce uncertainties in flood frequency studies.

Simulations of Sulfate-Nitrate-Ammonium (SNA) aerosols during the extreme haze events over Northern China in 2014

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Dan; Liu, Zhiquan; Fast, Jerome D.

Extreme haze events have occurred frequently over China in recent years. Although many studies have investigated the formation mechanisms associated with PM2.5 for heavily polluted regions in China based on observational data, adequately predicting peak PM2.5 concentrations is still challenging for regional air quality models. In this study, we evaluate the performance of one configuration of the Weather Research and Forecasting model coupled with chemistry (WRF-Chem) and use the model to investigate the sensitivity of heterogeneous reactions on simulated peak sulfate, nitrate, and ammonium concentrations in the vicinity of Beijing during four extreme haze episodes in October 2014 over themore » North China Plain. The highest observed PM2.5 concentration of 469 μg m-3 occurred in Beijing. Comparisons with observations show that the model reproduced the temporal variability in PM2.5 with the highest PM2.5 values on polluted days (defined as days in which observed PM2.5 is greater than 75 μg m-3), but predictions of sulfate, nitrate, and ammonium were too low on days with the highest observed concentrations. Observational data indicate that the sulfur/nitric oxidation rates are strongly correlated with relative humidity during periods of peak PM2.5; however, the model failed to reproduce the highest PM2.5 concentrations due to missing heterogeneous reactions. As the parameterizations of those reactions is not well established yet, estimates of SO2-to-H2SO4 and NO2/NO3-to-HNO3 reaction rates that depend on relative humidity were applied which improved the simulation of sulfate, nitrate, and ammonium enhancement on polluted days in terms of both concentrations and partitioning among those species. Sensitivity simulations showed that the extremely high heterogeneous reaction rates and also higher emission rates than those reported in the emission inventory« less

Soft Tissue Sarcoma—Health Professional Version

Cancer.gov

Soft tissue sarcomas are malignant tumors that arise in any of the mesodermal tissues of the extremities, trunk and retroperitoneum, or head and neck. Soft tissue sarcomas may be heterogeneous. Find evidence-based information on soft tissue sarcoma treatment and research.

Diagnostic accuracy of history, physical examination, and bedside ultrasound for diagnosis of extremity fractures in the emergency department: a systematic review.

PubMed

Joshi, Nikita; Lira, Alena; Mehta, Ninfa; Paladino, Lorenzo; Sinert, Richard

2013-01-01

Understanding history, physical examination, and ultrasonography (US) to diagnose extremity fractures compared with radiography has potential benefits of decreasing radiation exposure, costs, and pain and improving emergency department (ED) resource management and triage time. The authors performed two electronic searches using PubMed and EMBASE databases for studies published between 1965 to 2012 using a strategy based on the inclusion of any patient presenting with extremity injuries suspicious for fracture who had history and physical examination and a separate search for US performed by an emergency physician (EP) with subsequent radiography. The primary outcome was operating characteristics of ED history, physical examination, and US in diagnosing radiologically proven extremity fractures. The methodologic quality of the studies was assessed using the quality assessment of studies of diagnostic accuracy tool (QUADAS-2). Nine studies met the inclusion criteria for history and physical examination, while eight studies met the inclusion criteria for US. There was significant heterogeneity in the studies that prevented data pooling. Data were organized into subgroups based on anatomic fracture locations, but heterogeneity within the subgroups also prevented data pooling. The prevalence of fracture varied among the studies from 22% to 70%. Upper extremity physical examination tests have positive likelihood ratios (LRs) ranging from 1.2 to infinity and negative LRs ranging from 0 to 0.8. US sensitivities varied between 85% and 100%, specificities varied between 73% and 100%, positive LRs varied between 3.2 and 56.1, and negative LRs varied between 0 and 0.2. Compared with radiography, EP US is an accurate diagnostic test to rule in or rule out extremity fractures. The diagnostic accuracy for history and physical examination are inconclusive. Future research is needed to understand the accuracy of ED US when combined with history and physical examination for upper and lower extremity fractures. © 2013 by the Society for Academic Emergency Medicine.

Osteomalacia-inducing renal clear cell carcinoma uncovered by 99mTc-Hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) scintigraphy.

PubMed

Jin, Xiaona; Jing, Hongli; Li, Fang; Zhuang, Hongming

2013-11-01

Most osteomalacia-causing tumors are small, benign mesenchymal neoplasms, which are commonly located in the extremities or craniofacial regions. An 18-year-old male patient with suspicion of tumor-induced osteomalacia underwent (99m)Tc-HYNIC-TOC scintigraphy to search potential culprit tumor. The images showed a large activity in the region of the left kidney. The lesion was resected and a clear cell renal cell carcinoma was found. One year after the left nephrectomy, the patient was tumor-free without symptoms of osteomalacia.

Criticality and Induction Time of Hot Spots in Detonating Heterogeneous Explosives

NASA Astrophysics Data System (ADS)

Hill, Larry

2017-06-01

Detonation reaction in physically heterogeneous explosives is-to an extent that depends on multiple material attributes-likewise heterogeneous. Like all heterogeneous reaction, detonation heterogeneous reaction begins at nucleation sites, which, in this case, comprise localized regions of higher-than-average temperature-so-called hot spots. Burning grows at, and then spreads from these nucleation sites, via reactive-thermal (R-T) waves, to consume the interstitial material. Not all hot spots are consequential, but only those that are 1) supercritical, and 2) sufficiently so as to form R-T waves before being consumed by those already emanating from neighboring sites. I explore aspects of these two effects by deriving simple formulae for hot spot criticality and the induction time of supercritical hot spots. These results serve to illustrate the non-intuitive, yet mathematically simplifying, effects of extreme dependence of reaction rate upon temperature. They can play a role in the development of better reactive burn models, for which we seek to homogenize the essentials of heterogeneous detonation reaction without introducing spurious complexity. Work supported by the US Dept. of Energy.

Extreme Heterogeneity in Parasitism Despite Low Population Genetic Structure among Monarch Butterflies Inhabiting the Hawaiian Islands

PubMed Central

Pierce, Amanda A.; de Roode, Jacobus C.; Altizer, Sonia; Bartel, Rebecca A.

2014-01-01

Host movement and spatial structure can strongly influence the ecology and evolution of infectious diseases, with limited host movement potentially leading to high spatial heterogeneity in infection. Monarch butterflies (Danaus plexippus) are best known for undertaking a spectacular long-distance migration in eastern North America; however, they also form non-migratory populations that breed year-round in milder climates such as Hawaii and other tropical locations. Prior work showed an inverse relationship between monarch migratory propensity and the prevalence of the protozoan parasite, Ophryocystis elektroscirrha. Here, we sampled monarchs from replicate sites within each of four Hawaiian Islands to ask whether these populations show consistently high prevalence of the protozoan parasite as seen for monarchs from several other non-migratory populations. Counter to our predictions, we observed striking spatial heterogeneity in parasite prevalence, with infection rates per site ranging from 4–85%. We next used microsatellite markers to ask whether the observed variation in infection might be explained by limited host movement and spatial sub-structuring among sites. Our results showed that monarchs across the Hawaiian Islands form one admixed population, supporting high gene flow among sites. Moreover, measures of individual-level genetic diversity did not predict host infection status, as might be expected if more inbred hosts harbored higher parasite loads. These results suggest that other factors such as landscape-level environmental variation or colonization-extinction processes might instead cause the extreme heterogeneity in monarch butterfly infection observed here. PMID:24926796

Law of corresponding states for open collaborations

NASA Astrophysics Data System (ADS)

Gherardi, Marco; Bassetti, Federico; Cosentino Lagomarsino, Marco

2016-04-01

We study the relation between number of contributors and product size in Wikipedia and GitHub. In contrast to traditional production, this is strongly probabilistic, but is characterized by two quantitative nonlinear laws: a power-law bound to product size for increasing number of contributors, and the universal collapse of rescaled distributions. A variant of the random-energy model shows that both laws are due to the heterogeneity of contributors, and displays an intriguing finite-size scaling property with no equivalent in standard systems. The analysis uncovers the right intensive densities, enabling the comparison of projects with different numbers of contributors on equal grounds. We use this property to expose the detrimental effects of conflicting interactions in Wikipedia.

Cluster and Multiple Correspondence Analyses in Rheumatology: Paths to Uncovering Relationships in a Sea of Data.

PubMed

Han, Lu; Benseler, Susanne M; Tyrrell, Pascal N

2018-05-01

Rheumatic diseases encompass a wide range of conditions caused by inflammation and dysregulation of the immune system resulting in organ damage. Research in these heterogeneous diseases benefits from multivariate methods. The aim of this review was to describe and evaluate current literature in rheumatology regarding cluster analysis and correspondence analysis. A systematic review showed an increase in studies making use of these 2 methods. However, standardization in how these methods are applied and reported is needed. Researcher expertise was determined to be the main barrier to considering these approaches, whereas education and collaborating with a biostatistician were suggested ways forward. Copyright © 2018 Elsevier Inc. All rights reserved.

[Inherited thrombocytopenias].

PubMed

Leverger, G; Petit, A; Fasola, S; Landman-Parker, J; Favier, R

2010-08-01

Secondary causes of thrombocytopenia as immunologic thrombopenia purpura, or ITP, are far more common than inherited causes, which even as a group, are rare. Nevertheless, diagnosis is important and progress made in uncovering the molecular basis of these disorders has contributed greatly to our knowledge of these diseases. Inherited thrombocytopenias are a heterogeneous group of disorders. Different criteria have been suggested to classify the forms, such as the inheritance mechanism and the platelet volume as well as the associated platelet dysfunctions or clinical abnormality. This paper describes the clinical and biological data, and current knowledge of the molecular findings of inherited thrombocytopenia, allowing a diagnostic approach to these diseases. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

High-resolution Identification and Separation of Living Cell Types by Multiple microRNA-responsive Synthetic mRNAs.

PubMed

Endo, Kei; Hayashi, Karin; Saito, Hirohide

2016-02-23

The precise identification and separation of living cell types is critical to both study cell function and prepare cells for medical applications. However, intracellular information to distinguish live cells remains largely inaccessible. Here, we develop a method for high-resolution identification and separation of cell types by quantifying multiple microRNA (miRNA) activities in live cell populations. We found that a set of miRNA-responsive, in vitro synthesized mRNAs identify a specific cell population as a sharp peak and clearly separate different cell types based on less than two-fold differences in miRNA activities. Increasing the number of miRNA-responsive mRNAs enhanced the capability for cell identification and separation, as we precisely and simultaneously distinguished different cell types with similar miRNA profiles. In addition, the set of synthetic mRNAs separated HeLa cells into subgroups, uncovering heterogeneity of the cells and the level of resolution achievable. Our method could identify target live cells and improve the efficiency of cell purification from heterogeneous populations.

Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario.

PubMed

Ali, Muhammad Umar; Rahman, Muhammad Saif Ur; Cao, Jiang; Yuan, Ping Xi

2017-08-01

Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X-linked, autosomal dominant or autosomal recessive manner. To date 58 genes have been reported to associate with retinitis pigmentosa most of them are either expressed in photoreceptors or the retinal pigment epithelium. This review focuses on the disease mechanisms and genetics of retinitis pigmentosa. As retinitis pigmentosa is tremendously heterogeneous disorder expressing a multiplicity of mutations; different variations in the same gene might induce different disorders. In recent years, latest technologies including whole-exome sequencing contributing effectively to uncover the hidden genesis of retinitis pigmentosa by reporting new genetic mutations. In future, these advancements will help in better understanding the genotype-phenotype correlations of disease and likely to develop new therapies.

Genomic alterations and molecular subtypes of gastric cancers in Asians.

PubMed

Ye, Xiang S; Yu, Chunping; Aggarwal, Amit; Reinhard, Christoph

2016-05-09

Gastric cancer (GC) is a highly heterogenic disease, and it is the second leading cause of cancer death in the world. Common chemotherapies are not very effective for GC, which often presents as an advanced or metastatic disease at diagnosis. Treatment options are limited, and the prognosis for advanced GCs is poor. The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs, including studies that focused exclusively on GCs in Asians. These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs. An analysis of gene expression data by the Asian Cancer Research Group (ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development. In this article, we review the ACRG GC project. We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

PubMed Central

Shaheen, Ranad; Faqeih, Eissa; Alshammari, Muneera J; Swaid, Abdulrahman; Al-Gazali, Lihadh; Mardawi, Elham; Ansari, Shinu; Sogaty, Sameera; Seidahmed, Mohammed Z; AlMotairi, Muhammed I; Farra, Chantal; Kurdi, Wesam; Al-Rasheed, Shatha; Alkuraya, Fowzan S

2013-01-01

Meckel–Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n=12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis–van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population. PMID:23169490

Method Designed to Respect Molecular Heterogeneity Can Profoundly Correct Present Data Interpretations for Genome-Wide Expression Analysis

PubMed Central

Chen, Chih-Hao; Hsu, Chueh-Lin; Huang, Shih-Hao; Chen, Shih-Yuan; Hung, Yi-Lin; Chen, Hsiao-Rong; Wu, Yu-Chung

2015-01-01

Although genome-wide expression analysis has become a routine tool for gaining insight into molecular mechanisms, extraction of information remains a major challenge. It has been unclear why standard statistical methods, such as the t-test and ANOVA, often lead to low levels of reproducibility, how likely applying fold-change cutoffs to enhance reproducibility is to miss key signals, and how adversely using such methods has affected data interpretations. We broadly examined expression data to investigate the reproducibility problem and discovered that molecular heterogeneity, a biological property of genetically different samples, has been improperly handled by the statistical methods. Here we give a mathematical description of the discovery and report the development of a statistical method, named HTA, for better handling molecular heterogeneity. We broadly demonstrate the improved sensitivity and specificity of HTA over the conventional methods and show that using fold-change cutoffs has lost much information. We illustrate the especial usefulness of HTA for heterogeneous diseases, by applying it to existing data sets of schizophrenia, bipolar disorder and Parkinson’s disease, and show it can abundantly and reproducibly uncover disease signatures not previously detectable. Based on 156 biological data sets, we estimate that the methodological issue has affected over 96% of expression studies and that HTA can profoundly correct 86% of the affected data interpretations. The methodological advancement can better facilitate systems understandings of biological processes, render biological inferences that are more reliable than they have hitherto been and engender translational medical applications, such as identifying diagnostic biomarkers and drug prediction, which are more robust. PMID:25793610

A latent class analysis of drug abuse in a national Swedish sample.

PubMed

Kendler, K S; Ohlsson, H; Sundquist, K; Sundquist, J

2013-10-01

Drug abuse (DA) is a clinically heterogeneous syndrome. Using medical, legal, death and pharmacy records covering the entire population of Sweden, could we uncover meaningful subtypes of DA? We performed a latent class analysis (LCA) on all individuals in Sweden born 1950–1993 who were registered with DA or its consequences (n=192,501) and then validated these classes using demographics, patterns of co-morbidity with alcohol use disorder (AUD), non-DA crime and psychiatric illness, and the pattern of aggregation and co-aggregation in sibling pairs. The best-fit LCA had six classes : (1) low-frequency pure criminal, (2) high-frequency medical criminal, (3) low-frequency pure medical, (4) high-frequency medical, (5) prescription and (6) death. Each class had a distinct pattern of demographic features and co-morbidity and aggregated within sibling pairs with at least moderate specificity. For example, class 2 was characterized by early age at registration, low educational attainment, high male preponderance, high rates of AUDs, strong resemblance within sibling pairs [odds ratio (OR) 12.6] and crime and the highest risk for DA in siblings (20.0%). By contrast, class 5 had a female preponderance, late age at registration, low rates of crime and AUDs, high rates of psychiatric illness, high familiality within sibling pairs (OR 14.7) but the lowest observed risk for DA in siblings (8.9%). DA as assessed by public records is a heterogeneous syndrome. Familial factors contribute substantially to this heterogeneity. Advances in our understanding of etiological processes leading to DA will be aided by a consideration of this heterogeneity.

Extreme-scale Algorithms and Solver Resilience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dongarra, Jack

A widening gap exists between the peak performance of high-performance computers and the performance achieved by complex applications running on these platforms. Over the next decade, extreme-scale systems will present major new challenges to algorithm development that could amplify this mismatch in such a way that it prevents the productive use of future DOE Leadership computers due to the following; Extreme levels of parallelism due to multicore processors; An increase in system fault rates requiring algorithms to be resilient beyond just checkpoint/restart; Complex memory hierarchies and costly data movement in both energy and performance; Heterogeneous system architectures (mixing CPUs, GPUs,more » etc.); and Conflicting goals of performance, resilience, and power requirements.« less

Adaptation to climate change: Using nighttime lights satellite data to explore human response to flood events

NASA Astrophysics Data System (ADS)

Mård, Johanna; Di Baldassarre, Giuliano

2017-04-01

To better understand the impact of climate change, we need to uncover how (and to what extent) societies respond and adapt to it. Yet the dynamics resulting from two-way feedbacks between nature and society remain largely unknown. Here we present an interdisciplinary study aiming to uncover one of the least quantified aspects of human-nature interactions, the spatial-temporal distribution of demographic changes following the occurrence of extreme events. To this end, we use nighttime light satellite data in four contrasting case studies in both low- and high-income countries (Lower Limpopo River in Mozambique, Mekong River in Vietnam and Cambodia, Brisbane River in Australia and Mississippi River at St. Louis in USA), and explore the interplay between flooding events and changes in population distribution in the period 1992-2013. Our study shows the challenges and opportunities of nighttime lights in unraveling the way humans adapt to climate change. Specific results show that population distribution of societies that strongly rely on structural measures ("fighting floods" policies) is not significantly affected by the occurrence of flood events. Conversely, learning dynamics emerge in societies that mainly rely on non-structural measures ("living with floods" policies) in terms of relative population in floodplain areas, i.e. reduced human proximity to rivers. Lastly, we propose the development of a novel approach to exploit the growing availability of worldwide information, such as nighttime lights satellite data, to uncover human adaptation to climate change across scales and along gradients of social and natural conditions.

Using Kriging with a heterogeneous measurement error to improve the accuracy of extreme precipitation return level estimation

NASA Astrophysics Data System (ADS)

Yin, Shui-qing; Wang, Zhonglei; Zhu, Zhengyuan; Zou, Xu-kai; Wang, Wen-ting

2018-07-01

Extreme precipitation can cause flooding and may result in great economic losses and deaths. The return level is a commonly used measure of extreme precipitation events and is required for hydrological engineer designs, including those of sewerage systems, dams, reservoirs and bridges. In this paper, we propose a two-step method to estimate the return level and its uncertainty for a study region. In the first step, we use the generalized extreme value distribution, the L-moment method and the stationary bootstrap to estimate the return level and its uncertainty at the site with observations. In the second step, a spatial model incorporating the heterogeneous measurement errors and covariates is trained to estimate return levels at sites with no observations and to improve the estimates at sites with limited information. The proposed method is applied to the daily rainfall data from 273 weather stations in the Haihe river basin of North China. We compare the proposed method with two alternatives: the first one is based on the ordinary Kriging method without measurement error, and the second one smooths the estimated location and scale parameters of the generalized extreme value distribution by the universal Kriging method. Results show that the proposed method outperforms its counterparts. We also propose a novel approach to assess the two-step method by comparing it with the at-site estimation method with a series of reduced length of observations. Estimates of the 2-, 5-, 10-, 20-, 50- and 100-year return level maps and the corresponding uncertainties are provided for the Haihe river basin, and a comparison with those released by the Hydrology Bureau of Ministry of Water Resources of China is made.

Correlating Microbial Diversity Patterns with Geochemistry in an Extreme and Heterogeneous Environment of Mine Tailings

PubMed Central

Liu, Jun; Hua, Zheng-Shuang; Chen, Lin-Xing; Kuang, Jia-Liang; Li, Sheng-Jin; Shu, Wen-Sheng

2014-01-01

Recent molecular surveys have advanced our understanding of the forces shaping the large-scale ecological distribution of microbes in Earth's extreme habitats, such as hot springs and acid mine drainage. However, few investigations have attempted dense spatial analyses of specific sites to resolve the local diversity of these extraordinary organisms and how communities are shaped by the harsh environmental conditions found there. We have applied a 16S rRNA gene-targeted 454 pyrosequencing approach to explore the phylogenetic differentiation among 90 microbial communities from a massive copper tailing impoundment generating acidic drainage and coupled these variations in community composition with geochemical parameters to reveal ecological interactions in this extreme environment. Our data showed that the overall microbial diversity estimates and relative abundances of most of the dominant lineages were significantly correlated with pH, with the simplest assemblages occurring under extremely acidic conditions and more diverse assemblages associated with neutral pHs. The consistent shifts in community composition along the pH gradient indicated that different taxa were involved in the different acidification stages of the mine tailings. Moreover, the effect of pH in shaping phylogenetic structure within specific lineages was also clearly evident, although the phylogenetic differentiations within the Alphaproteobacteria, Deltaproteobacteria, and Firmicutes were attributed to variations in ferric and ferrous iron concentrations. Application of the microbial assemblage prediction model further supported pH as the major factor driving community structure and demonstrated that several of the major lineages are readily predictable. Together, these results suggest that pH is primarily responsible for structuring whole communities in the extreme and heterogeneous mine tailings, although the diverse microbial taxa may respond differently to various environmental conditions. PMID:24727268

heterogeneous mixture distributions for multi-source extreme rainfall

NASA Astrophysics Data System (ADS)

Ouarda, T.; Shin, J.; Lee, T. S.

2013-12-01

Mixture distributions have been used to model hydro-meteorological variables showing mixture distributional characteristics, e.g. bimodality. Homogeneous mixture (HOM) distributions (e.g. Normal-Normal and Gumbel-Gumbel) have been traditionally applied to hydro-meteorological variables. However, there is no reason to restrict the mixture distribution as the combination of one identical type. It might be beneficial to characterize the statistical behavior of hydro-meteorological variables from the application of heterogeneous mixture (HTM) distributions such as Normal-Gamma. In the present work, we focus on assessing the suitability of HTM distributions for the frequency analysis of hydro-meteorological variables. In the present work, in order to estimate the parameters of HTM distributions, the meta-heuristic algorithm (Genetic Algorithm) is employed to maximize the likelihood function. In the present study, a number of distributions are compared, including the Gamma-Extreme value type-one (EV1) HTM distribution, the EV1-EV1 HOM distribution, and EV1 distribution. The proposed distribution models are applied to the annual maximum precipitation data in South Korea. The Akaike Information Criterion (AIC), the root mean squared errors (RMSE) and the log-likelihood are used as measures of goodness-of-fit of the tested distributions. Results indicate that the HTM distribution (Gamma-EV1) presents the best fitness. The HTM distribution shows significant improvement in the estimation of quantiles corresponding to the 20-year return period. It is shown that extreme rainfall in the coastal region of South Korea presents strong heterogeneous mixture distributional characteristics. Results indicate that HTM distributions are a good alternative for the frequency analysis of hydro-meteorological variables when disparate statistical characteristics are presented.

Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity.

PubMed

Grünewald, Inga; Vollbrecht, Claudia; Meinrath, Jeannine; Meyer, Moritz F; Heukamp, Lukas C; Drebber, Uta; Quaas, Alexander; Beutner, Dirk; Hüttenbrink, Karl-Bernd; Wardelmann, Eva; Hartmann, Wolfgang; Büttner, Reinhard; Odenthal, Margarete; Stenner, Markus

2015-07-20

Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.

Flexibility Matters: Cooperative Active Sites in Covalent Organic Framework and Threaded Ionic Polymer.

PubMed

Sun, Qi; Aguila, Briana; Perman, Jason; Nguyen, Nicholas; Ma, Shengqian

2016-12-07

The combination of two or more reactive centers working in concert on a substrate to facilitate the reaction is now considered state of the art in catalysis, yet there still remains a tremendous challenge. Few heterogeneous systems of this sort have been exploited, as the active sites spatially separated within the rigid framework are usually difficult to cooperate. It is now shown that this roadblock can be surpassed. The underlying principle of the strategy presented here is the integration of catalytic components with excellent flexibility and porous heterogeneous catalysts, as demonstrated by the placement of linear ionic polymers in close proximity to surface Lewis acid active sites anchored on the walls of a covalent organic framework (COF). Using the cycloaddition of the epoxides and CO 2 as a model reaction, dramatic activity improvements have been achieved for the composite catalysts in relation to the individual catalytic component. Furthermore, they also clearly outperform the benchmark catalytic systems formed by the combination of the molecular organocatalysts and heterogeneous Lewis acid catalysts, while affording additional recyclability. The extraordinary flexibility and enriched concentration of the catalytically active moieties on linear polymers facilitate the concerted catalysis, thus leading to superior catalytic performance. This work therefore uncovers an entirely new strategy for designing bifunctional catalysts with double-activation behavior and opens a new avenue in the design of multicapable systems that mimic biocatalysis.

Metagenomic Analysis of Hot Springs in Central India Reveals Hydrocarbon Degrading Thermophiles and Pathways Essential for Survival in Extreme Environments

PubMed Central

Saxena, Rituja; Dhakan, Darshan B.; Mittal, Parul; Waiker, Prashant; Chowdhury, Anirban; Ghatak, Arundhuti; Sharma, Vineet K.

2017-01-01

Extreme ecosystems such as hot springs are of great interest as a source of novel extremophilic species, enzymes, metabolic functions for survival and biotechnological products. India harbors hundreds of hot springs, the majority of which are not yet explored and require comprehensive studies to unravel their unknown and untapped phylogenetic and functional diversity. The aim of this study was to perform a large-scale metagenomic analysis of three major hot springs located in central India namely, Badi Anhoni, Chhoti Anhoni, and Tattapani at two geographically distinct regions (Anhoni and Tattapani), to uncover the resident microbial community and their metabolic traits. Samples were collected from seven distinct sites of the three hot spring locations with temperature ranging from 43.5 to 98°C. The 16S rRNA gene amplicon sequencing of V3 hypervariable region and shotgun metagenome sequencing uncovered a unique taxonomic and metabolic diversity of the resident thermophilic microbial community in these hot springs. Genes associated with hydrocarbon degradation pathways, such as benzoate, xylene, toluene, and benzene were observed to be abundant in the Anhoni hot springs (43.5–55°C), dominated by Pseudomonas stutzeri and Acidovorax sp., suggesting the presence of chemoorganotrophic thermophilic community with the ability to utilize complex hydrocarbons as a source of energy. A high abundance of genes belonging to methane metabolism pathway was observed at Chhoti Anhoni hot spring, where methane is reported to constitute >80% of all the emitted gases, which was marked by the high abundance of Methylococcus capsulatus. The Tattapani hot spring, with a high-temperature range (61.5–98°C), displayed a lower microbial diversity and was primarily dominated by a nitrate-reducing archaeal species Pyrobaculum aerophilum. A higher abundance of cell metabolism pathways essential for the microbial survival in extreme conditions was observed at Tattapani. Taken together, the results of this study reveal a novel consortium of microbes, genes, and pathways associated with the hot spring environment. PMID:28105025

Editor's Choice - Incidence of Stroke Following Thoracic Endovascular Aortic Repair for Descending Aortic Aneurysm: A Systematic Review of the Literature with Meta-analysis.

PubMed

von Allmen, R S; Gahl, B; Powell, J T

2017-02-01

Stroke is an increasingly recognised complication following thoracic endovascular aortic repair (TEVAR). The aim of this study was to systematically synthesise the published data on perioperative stroke incidence during TEVAR for patients with descending thoracic aneurysmal disease and to assess the impact of left subclavian artery (LSA) coverage on stroke incidence. A systematic review of English and German articles on perioperative (in-hospital or 30 day) stroke incidence following TEVAR for descending aortic aneurysm was performed, including studies with ≥50 cases, using MEDLINE and EMBASE (2005-2015). The pooled prevalence of perioperative stroke with 95% CI was estimated using random effect analysis. Heterogeneity was examined using I 2 statistic. Of 215 studies identified, 10 were considered suitable for inclusion. The included studies enrolled a total of 2594 persons (61% male) between 1997 and 2014 with a mean weighted age of 71.8 (95% CI 71.1-73.6) years. The pooled prevalence for stroke was 4.1% (95% CI 2.9-5.5) with moderate heterogeneity between studies (I 2  = 49.8%, p = .04). Five studies reported stroke incidences stratified by the management of the LSA, that is uncovered versus covered and revascularised versus covered and not-revascularised. In cases where the LSA remained uncovered, the pooled stroke incidence was 3.2% (95% CI 1.0-6.5). There was, however, an indication that stroke incidence increased following LSA coverage, to 5.3% (95% CI 2.6-8.6) in those with a revascularisation and 8.0% (95% CI 4.1-12.9) in those without revascularisation. Stroke incidence is an important morbidity after TEVAR, and probably increases if the LSA is covered during the procedure, particularly in those without revascularisation. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Genome Reduction Uncovers a Large Dispensable Genome and Adaptive Role for Copy Number Variation in Asexually Propagated Solanum tuberosum[OPEN

PubMed Central

Hardigan, Michael A.; Crisovan, Emily; Hamilton, John P.; Laimbeer, Parker; Leisner, Courtney P.; Manrique-Carpintero, Norma C.; Newton, Linsey; Pham, Gina M.; Vaillancourt, Brieanne; Zeng, Zixian; Jiang, Jiming

2016-01-01

Clonally reproducing plants have the potential to bear a significantly greater mutational load than sexually reproducing species. To investigate this possibility, we examined the breadth of genome-wide structural variation in a panel of monoploid/doubled monoploid clones generated from native populations of diploid potato (Solanum tuberosum), a highly heterozygous asexually propagated plant. As rare instances of purely homozygous clones, they provided an ideal set for determining the degree of structural variation tolerated by this species and deriving its minimal gene complement. Extensive copy number variation (CNV) was uncovered, impacting 219.8 Mb (30.2%) of the potato genome with nearly 30% of genes subject to at least partial duplication or deletion, revealing the highly heterogeneous nature of the potato genome. Dispensable genes (>7000) were associated with limited transcription and/or a recent evolutionary history, with lower deletion frequency observed in genes conserved across angiosperms. Association of CNV with plant adaptation was highlighted by enrichment in gene clusters encoding functions for environmental stress response, with gene duplication playing a part in species-specific expansions of stress-related gene families. This study revealed unique impacts of CNV in a species with asexual reproductive habits and how CNV may drive adaption through evolution of key stress pathways. PMID:26772996

An exploratory comparison of name generator content: Data from rural India.

PubMed

Shakya, Holly B; Christakis, Nicholas A; Fowler, James H

2017-01-01

Since the 1970s sociologists have explored the best means for measuring social networks, although few name generator analyses have used sociocentric data or data from developing countries, partly because sociocentric studies in developing countries have been scant. Here, we analyze 12 different name generators used in a sociocentric network study conducted in 75 villages in rural Karnataka, India. Having unusual sociocentric data from a non-Western context allowed us to extend previous name generator research through the unique analyses of network structural measures, an extensive consideration of homophily, and investigation of status difference between egos and alters. We found that domestic interaction questions generated networks that were highly clustered and highly centralized. Similarity between respondents and their nominated contacts was strongest for gender, caste, and religion. We also found that domestic interaction name generators yielded the most homogeneous ties, while advice questions yielded the most heterogeneous. Participants were generally more likely to nominate those of higher social status, although certain questions, such as who participants talk to uncovered more egalitarian relationships, while other name generators elicited the names of social contacts distinctly higher or lower in status than the respondent. Some questions also seemed to uncover networks that were specific to the cultural context, suggesting that network researchers should balance local relevance with global generalizability when choosing name generators.

Partial differential equation techniques for analysing animal movement: A comparison of different methods.

PubMed

Wang, Yi-Shan; Potts, Jonathan R

2017-03-07

Recent advances in animal tracking have allowed us to uncover the drivers of movement in unprecedented detail. This has enabled modellers to construct ever more realistic models of animal movement, which aid in uncovering detailed patterns of space use in animal populations. Partial differential equations (PDEs) provide a popular tool for mathematically analysing such models. However, their construction often relies on simplifying assumptions which may greatly affect the model outcomes. Here, we analyse the effect of various PDE approximations on the analysis of some simple movement models, including a biased random walk, central-place foraging processes and movement in heterogeneous landscapes. Perhaps the most commonly-used PDE method dates back to a seminal paper of Patlak from 1953. However, our results show that this can be a very poor approximation in even quite simple models. On the other hand, more recent methods, based on transport equation formalisms, can provide more accurate results, as long as the kernel describing the animal's movement is sufficiently smooth. When the movement kernel is not smooth, we show that both the older and newer methods can lead to quantitatively misleading results. Our detailed analysis will aid future researchers in the appropriate choice of PDE approximation for analysing models of animal movement. Copyright © 2017 Elsevier Ltd. All rights reserved.

Proteomic Analysis of Cytokeratin Isoforms Uncovers Association with Survival in Lung Adenocarcinoma1

PubMed Central

Gharib, Tarek G.; Chen, Guoan; Wang, Hong; Huang, Chiang-Ching; Prescott, Michael S.; Shedden, Kerby; Misek, David E.; Thomas, Dafydd G.; Giordano, Thomas J.; Taylor, Jeremy M.G.; Kardia, Sharon; Yee, John; Orringer, Mark B.; Hanash, Samir; Beer, David G.

2002-01-01

Abstract Cytokeratins (CK) are intermediate filaments whose expression is often altered in epithelial cancer. Systematic identification of lung adenocarcinoma proteins using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry has uncovered numerous CK isoforms. In this study, 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung samples were quantitatively examined for protein expression. Fourteen of 21 isoforms of CK 7, 8, 18, and 19 occurred at significantly higher levels (P<.05) in tumors compared to uninvolved adjacent tissue. Specific isoforms of the four types of CK identified correlated with either clinical outcome or individual clinical-pathological parameters. All five of the CK7 isoforms associated with patient survival represented cleavage products. Two of five CK7 isoforms (nos. 2165 and 2091), one of eight CK8 isoforms (no. 439), and one of three CK19 isoforms (no. 1955) were associated with survival and significantly correlated to their mRNA levels, suggesting that transcription underlies overexpression of these CK isoforms. Our data indicate substantial heterogeneity among CK in lung adenocarcinomas resulting from posttranslational modifications, some of which correlated with patient survival and other clinical parameters. Therefore, specific isoforms of individual CK may have utility as diagnostic or predictive markers in lung adenocarcinomas. PMID:12192603

Single-center experience of N-linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs.

PubMed

Bastaki, Fatma; Bizzari, Sami; Hamici, Sana; Nair, Pratibha; Mohamed, Madiha; Saif, Fatima; Malik, Ethar Mustafa; Al-Ali, Mahmoud Taleb; Hamzeh, Abdul Rezzak

2018-01-01

Congenital disorders of glycosylation (CDG) represent an expanding group of conditions that result from defects in protein and lipid glycosylation. Different subgroups of CDG display considerable clinical and genetic heterogeneity due to the highly complex nature of cellular glycosylation. This is further complicated by ethno-geographic differences in the mutational landscape of each of these subgroups. Ten Arab CDG patients from Latifa Hospital in Dubai, United Arab Emirates, were assessed using biochemical (glycosylation status of transferrin) and molecular approaches (next-generation sequencing [NGS] and Sanger sequencing). In silico tools including CADD and PolyPhen-2 were used to predict the functional consequences of uncovered mutations. In our sample of patients, five novel mutations were uncovered in the genes: MPDU1, PMM2, MAN1B1, and RFT1. In total, 9 mutations were harbored by the 10 patients in 7 genes. These are missense and nonsense mutations with deleterious functional consequences. This article integrates a single-center experience within a list of reported CDG mutations in the Arab world, accompanied by full molecular and clinical details pertaining to the studied cases. It also sheds light on potential ethnic differences that were not noted before in regards to CDG in the Arab world. © 2017 John Wiley & Sons Ltd/University College London.

Intercontinental difference in extreme weather events for the Northern Hemisphere over the past half century

NASA Astrophysics Data System (ADS)

Chen, A.; Tan, J.; Piao, S.

2014-12-01

Weather events that are located in the tails of a weather distribution are called weather extremes. Weather extremes, including severe drought, flooding, heat and cold waves, usually can cause greatest damage to human lives and properties, and have profound implication on ecosystem productivity and carbon cycles. There is mounting evidence suggests that the frequency of temperature and hydrological weather extremes have steadily increased over the last decades, largely due to the ongoing climate change. On the other hand, the distribution and trend of weather extremes can be regionally heterogeneous, which have not been well understood. Here we investigate the spatial distribution and temporal trend of weather extremes in the Northern Hemisphere (NH) over the past half century (1961-2010), with emphasis on the intercontinental comparisons. Our results suggest that warming extremes have increased significantly in East Asia and West Europe; while coldness extremes have decreased globally. Heavy precipitation extremes significantly increased in eastern Northern America, boreal Eurasia, and some parts of China; while drought events showed an increasing trend in northern China-southern Mongolia and some parts of western United States. Our results highlight the regional difference in the trend of weather extremes, which need to be incorporated in the mitigation measures.

Log-amplitude statistics for Beck-Cohen superstatistics

NASA Astrophysics Data System (ADS)

Kiyono, Ken; Konno, Hidetoshi

2013-05-01

As a possible generalization of Beck-Cohen superstatistical processes, we study non-Gaussian processes with temporal heterogeneity of local variance. To characterize the variance heterogeneity, we define log-amplitude cumulants and log-amplitude autocovariance and derive closed-form expressions of the log-amplitude cumulants for χ2, inverse χ2, and log-normal superstatistical distributions. Furthermore, we show that χ2 and inverse χ2 superstatistics with degree 2 are closely related to an extreme value distribution, called the Gumbel distribution. In these cases, the corresponding superstatistical distributions result in the q-Gaussian distribution with q=5/3 and the bilateral exponential distribution, respectively. Thus, our finding provides a hypothesis that the asymptotic appearance of these two special distributions may be explained by a link with the asymptotic limit distributions involving extreme values. In addition, as an application of our approach, we demonstrated that non-Gaussian fluctuations observed in a stock index futures market can be well approximated by the χ2 superstatistical distribution with degree 2.

Early studies reported extreme findings with large variability: a meta-epidemiologic study in the field of endocrinology.

PubMed

Wang, Zhen; Alahdab, Fares; Almasri, Jehad; Haydour, Qusay; Mohammed, Khaled; Abu Dabrh, Abd Moain; Prokop, Larry J; Alfarkh, Wedad; Lakis, Sumaya; Montori, Victor M; Murad, Mohammad Hassan

2016-04-01

To evaluate the presence of extreme findings and fluctuation in effect size in endocrinology. We systematically identified all meta-analyses published in 2014 in the field of endocrinology. Within each meta-analysis, the effect size of the primary binary outcome was compared across studies according to their order of publication. We pooled studies using the DerSimonian and Laird random-effects method. Heterogeneity was evaluated using the I(2) and tau(2). Twelve percent of the included 100 meta-analyses reported the largest effect size in the very first published study. The largest effect size occurred in the first 2 earliest studies in 31% of meta-analyses. When the effect size was the largest in the first published study, it was three times larger than the final pooled effect (ratio of rates, 3.26; 95% confidence interval: 1.80, 5.90). The largest heterogeneity measured by I(2) was observed in 18% of the included meta-analyses when combining the first 2 studies or 17% when combing the first 3 studies. In endocrinology, early studies reported extreme findings with large variability. This behavior of the evidence needs to be taken into account when used to formulate clinical policies. Copyright © 2016 Elsevier Inc. All rights reserved.

Combining Deterministic structures and stochastic heterogeneity for transport modeling

NASA Astrophysics Data System (ADS)

Zech, Alraune; Attinger, Sabine; Dietrich, Peter; Teutsch, Georg

2017-04-01

Contaminant transport in highly heterogeneous aquifers is extremely challenging and subject of current scientific debate. Tracer plumes often show non-symmetric but highly skewed plume shapes. Predicting such transport behavior using the classical advection-dispersion-equation (ADE) in combination with a stochastic description of aquifer properties requires a dense measurement network. This is in contrast to the available information for most aquifers. A new conceptual aquifer structure model is presented which combines large-scale deterministic information and the stochastic approach for incorporating sub-scale heterogeneity. The conceptual model is designed to allow for a goal-oriented, site specific transport analysis making use of as few data as possible. Thereby the basic idea is to reproduce highly skewed tracer plumes in heterogeneous media by incorporating deterministic contrasts and effects of connectivity instead of using unimodal heterogeneous models with high variances. The conceptual model consists of deterministic blocks of mean hydraulic conductivity which might be measured by pumping tests indicating values differing in orders of magnitudes. A sub-scale heterogeneity is introduced within every block. This heterogeneity can be modeled as bimodal or log-normal distributed. The impact of input parameters, structure and conductivity contrasts is investigated in a systematic manor. Furthermore, some first successful implementation of the model was achieved for the well known MADE site.

Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

NASA Astrophysics Data System (ADS)

Rose, P. B.; Erickson, A. S.; Mayer, M.; Nattress, J.; Jovanovic, I.

2016-04-01

Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method from being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.

Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rose, Jr., P. B.; Erickson, A. S.; Mayer, Michael F.

Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method frommore » being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.« less

Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

DOE PAGES

Rose, P. B.; Erickson, A. S.; Mayer, M.; ...

2016-04-18

Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method frommore » being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.« less

Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

PubMed Central

Rose, P. B.; Erickson, A. S.; Mayer, M.; Nattress, J.; Jovanovic, I.

2016-01-01

Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method from being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications. PMID:27087555

Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging.

PubMed

Rose, P B; Erickson, A S; Mayer, M; Nattress, J; Jovanovic, I

2016-04-18

Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as "searching for a needle in a haystack" because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method from being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material's areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.

Medical dosimetry in Hungary

NASA Astrophysics Data System (ADS)

Turák, O.; Osvay, M.; Ballay, L.

2012-09-01

Radiation exposure of medical staff during cardiological and radiological procedures was investigated. The exposure of medical staff is directly connected to patient exposure. The aim of this study was to determine the distribution of doses on uncovered part of body of medical staff using LiF thermoluminescent (TL) dosimeters in seven locations. Individual Kodak film dosimeters (as authorized dosimetry system) were used for the assessment of medical staff's effective dose. Results achieved on dose distribution measurements confirm that wearing only one film badge under the lead apron does not provide enough information on the personal dose. The value of estimated annual doses on eye lens and extremities (fingers) were in good correlation with international publications.

Long-distance measurement-device-independent multiparty quantum communication.

PubMed

Fu, Yao; Yin, Hua-Lei; Chen, Teng-Yun; Chen, Zeng-Bing

2015-03-06

The Greenberger-Horne-Zeilinger (GHZ) entanglement, originally introduced to uncover the extreme violation of local realism against quantum mechanics, is an important resource for multiparty quantum communication tasks. But the low intensity and fragility of the GHZ entanglement source in current conditions have made the practical applications of these multiparty tasks an experimental challenge. Here we propose a feasible scheme for practically distributing the postselected GHZ entanglement over a distance of more than 100 km for experimentally accessible parameter regimes. Combining the decoy-state and measurement-device-independent protocols for quantum key distribution, we anticipate that our proposal suggests an important avenue for practical multiparty quantum communication.

KSC-08pd0646

NASA Image and Video Library

2008-03-05

KENNEDY SPACE CENTER, FLA. -- In the Astrotech payload processing facility, NASA's Gamma-Ray Large Area Space Telescope, or GLAST, sits uncovered before its move to a work stand in the facility for a complete checkout of the scientific instruments aboard. The telescope will launch aboard a Delta II rocket May 16 from Launch Pad 17-B on Cape Canaveral Air Force Station. A powerful space observatory, the GLAST will explore the most extreme environments in the universe, and answer questions about supermassive black hole systems, pulsars and the origin of cosmic rays. It also will study the mystery of powerful explosions known as gamma-ray bursts. Photo credit: NASA/Kim Shiflett

Fiber Bragg Grating Dilatometry in Extreme Magnetic Field and Cryogenic Conditions

PubMed Central

Corvalán Moya, Carolina; Weickert, Franziska; Zapf, Vivien; Balakirev, Fedor F.; Wartenbe, Mark; Rosa, Priscila F. S.; Betts, Jonathan B.; Crooker, Scott A.; Daou, Ramzy

2017-01-01

In this work, we review single mode SiO2 fiber Bragg grating techniques for dilatometry studies of small single-crystalline samples in the extreme environments of very high, continuous, and pulsed magnetic fields of up to 150 T and at cryogenic temperatures down to <1 K. Distinct millimeter-long materials are measured as part of the technique development, including metallic, insulating, and radioactive compounds. Experimental strategies are discussed for the observation and analysis of the related thermal expansion and magnetostriction of materials, which can achieve a strain sensitivity (ΔL/L) as low as a few parts in one hundred million (≈10−8). The impact of experimental artifacts, such as those originating in the temperature dependence of the fiber’s index of diffraction, light polarization rotation in magnetic fields, and reduced strain transfer from millimeter-long specimens, is analyzed quantitatively using analytic models available in the literature. We compare the experimental results with model predictions in the small-sample limit, and discuss the uncovered discrepancies. PMID:29117137

Fiber Bragg Grating Dilatometry in Extreme Magnetic Field and Cryogenic Conditions.

PubMed

Jaime, Marcelo; Corvalán Moya, Carolina; Weickert, Franziska; Zapf, Vivien; Balakirev, Fedor F; Wartenbe, Mark; Rosa, Priscila F S; Betts, Jonathan B; Rodriguez, George; Crooker, Scott A; Daou, Ramzy

2017-11-08

In this work, we review single mode SiO₂ fiber Bragg grating techniques for dilatometry studies of small single-crystalline samples in the extreme environments of very high, continuous, and pulsed magnetic fields of up to 150 T and at cryogenic temperatures down to <1 K. Distinct millimeter-long materials are measured as part of the technique development, including metallic, insulating, and radioactive compounds. Experimental strategies are discussed for the observation and analysis of the related thermal expansion and magnetostriction of materials, which can achieve a strain sensitivity ( ΔL/L ) as low as a few parts in one hundred million (≈10 -8 ). The impact of experimental artifacts, such as those originating in the temperature dependence of the fiber's index of diffraction, light polarization rotation in magnetic fields, and reduced strain transfer from millimeter-long specimens, is analyzed quantitatively using analytic models available in the literature. We compare the experimental results with model predictions in the small-sample limit, and discuss the uncovered discrepancies.

Fiber Bragg Grating Dilatometry in Extreme Magnetic Field and Cryogenic Conditions

DOE PAGES

Jaime, Marcelo; Corvalán Moya, Carolina; Weickert, Franziska; ...

2017-11-08

In this work, we review single mode SiO 2 fiber Bragg grating techniques for dilatometry studies of small single-crystalline samples in the extreme environments of very high, continuous, and pulsed magnetic fields of up to 150 T and at cryogenic temperatures down to <1 K. Distinct millimeter-long materials are measured as part of the technique development, including metallic, insulating, and radioactive compounds. Experimental strategies are discussed for the observation and analysis of the related thermal expansion and magnetostriction of materials, which can achieve a strain sensitivity (ΔL/L) as low as a few parts in one hundred million (≈10 -8). Themore » impact of experimental artifacts, such as those originating in the temperature dependence of the fiber’s index of diffraction, light polarization rotation in magnetic fields, and reduced strain transfer from millimeter-long specimens, is analyzed quantitatively using analytic models available in the literature. We compare the experimental results with model predictions in the small-sample limit, and discuss the uncovered discrepancies.« less

Phylogenetic rooting using minimal ancestor deviation.

PubMed

Tria, Fernando Domingues Kümmel; Landan, Giddy; Dagan, Tal

2017-06-19

Ancestor-descendent relations play a cardinal role in evolutionary theory. Those relations are determined by rooting phylogenetic trees. Existing rooting methods are hampered by evolutionary rate heterogeneity or the unavailability of auxiliary phylogenetic information. Here we present a rooting approach, the minimal ancestor deviation (MAD) method, which accommodates heterotachy by using all pairwise topological and metric information in unrooted trees. We demonstrate the performance of the method, in comparison to existing rooting methods, by the analysis of phylogenies from eukaryotes and prokaryotes. MAD correctly recovers the known root of eukaryotes and uncovers evidence for the origin of cyanobacteria in the ocean. MAD is more robust and consistent than existing methods, provides measures of the root inference quality and is applicable to any tree with branch lengths.

Lessons from single-cell transcriptome analysis of oxygen-sensing cells.

PubMed

Zhou, Ting; Matsunami, Hiroaki

2018-05-01

The advent of single-cell RNA-sequencing (RNA-Seq) technology has enabled transcriptome profiling of individual cells. Comprehensive gene expression analysis at the single-cell level has proven to be effective in characterizing the most fundamental aspects of cellular function and identity. This unbiased approach is revolutionary for small and/or heterogeneous tissues like oxygen-sensing cells in identifying key molecules. Here, we review the major methods of current single-cell RNA-Seq technology. We discuss how this technology has advanced the understanding of oxygen-sensing glomus cells in the carotid body and helped uncover novel oxygen-sensing cells and mechanisms in the mice olfactory system. We conclude by providing our perspective on future single-cell RNA-Seq research directed at oxygen-sensing cells.

Envisioning migration: Mathematics in both experimental analysis and modeling of cell behavior

PubMed Central

Zhang, Elizabeth R.; Wu, Lani F.; Altschuler, Steven J.

2013-01-01

The complex nature of cell migration highlights the power and challenges of applying mathematics to biological studies. Mathematics may be used to create model equations that recapitulate migration, which can predict phenomena not easily uncovered by experiments or intuition alone. Alternatively, mathematics may be applied to interpreting complex data sets with better resolution—potentially empowering scientists to discern subtle patterns amid the noise and heterogeneity typical of migrating cells. Iteration between these two methods is necessary in order to reveal connections within the cell migration signaling network, as well as to understand the behavior that arises from those connections. Here, we review recent quantitative analysis and mathematical modeling approaches to the cell migration problem. PMID:23660413

TLM-Tracker: software for cell segmentation, tracking and lineage analysis in time-lapse microscopy movies.

PubMed

Klein, Johannes; Leupold, Stefan; Biegler, Ilona; Biedendieck, Rebekka; Münch, Richard; Jahn, Dieter

2012-09-01

Time-lapse imaging in combination with fluorescence microscopy techniques enable the investigation of gene regulatory circuits and uncovered phenomena like culture heterogeneity. In this context, computational image processing for the analysis of single cell behaviour plays an increasing role in systems biology and mathematical modelling approaches. Consequently, we developed a software package with graphical user interface for the analysis of single bacterial cell behaviour. A new software called TLM-Tracker allows for the flexible and user-friendly interpretation for the segmentation, tracking and lineage analysis of microbial cells in time-lapse movies. The software package, including manual, tutorial video and examples, is available as Matlab code or executable binaries at http://www.tlmtracker.tu-bs.de.

Envisioning migration: mathematics in both experimental analysis and modeling of cell behavior.

PubMed

Zhang, Elizabeth R; Wu, Lani F; Altschuler, Steven J

2013-10-01

The complex nature of cell migration highlights the power and challenges of applying mathematics to biological studies. Mathematics may be used to create model equations that recapitulate migration, which can predict phenomena not easily uncovered by experiments or intuition alone. Alternatively, mathematics may be applied to interpreting complex data sets with better resolution--potentially empowering scientists to discern subtle patterns amid the noise and heterogeneity typical of migrating cells. Iteration between these two methods is necessary in order to reveal connections within the cell migration signaling network, as well as to understand the behavior that arises from those connections. Here, we review recent quantitative analysis and mathematical modeling approaches to the cell migration problem. Copyright © 2013 Elsevier Ltd. All rights reserved.

Spatial and temporal trends of drought effects in a heterogeneous semi-arid forest ecosystem

USGS Publications Warehouse

Assal, Timothy J.; Anderson, Patrick J.; Sibold, Jason

2016-01-01

Drought has long been recognized as a driving mechanism in the forests of western North America and drought-induced mortality has been documented across genera in recent years. Given the frequency of these events are expected to increase in the future, understanding patterns of mortality and plant response to severe drought is important to resource managers. Drought can affect the functional, physiological, structural, and demographic properties of forest ecosystems. Remote sensing studies have documented changes in forest properties due to direct and indirect effects of drought; however, few studies have addressed this at local scales needed to characterize highly heterogeneous ecosystems in the forest-shrubland ecotone. We analyzed a 22-year Landsat time series (1985–2012) to determine changes in forest in an area that experienced a relatively dry decade punctuated by two years of extreme drought. We assessed the relationship between several vegetation indices and field measured characteristics (e.g. plant area index and canopy gap fraction) and applied these indices to trend analysis to uncover the location, direction and timing of change. Finally, we assessed the interaction of climate and topography by forest functional type. The Normalized Difference Moisture Index (NDMI), a measure of canopy water content, had the strongest correlation with short-term field measures of plant area index (R2 = 0.64) and canopy gap fraction (R2 = 0.65). Over the entire time period, 25% of the forested area experienced a significant (p-value < 0.05) negative trend in NDMI, compared to less than 10% in a positive trend. Coniferous forests were more likely to be associated with a negative NDMI trend than deciduous forest. Forests on southern aspects were least likely to exhibit a negative trend while north aspects were most prevalent. Field plots with a negative trend had a lower live density, and higher amounts of standing dead and down trees compared to plots with no trend. Our analysis identifies spatially explicit patterns of long-term trends anchored with ground based evidence to highlight areas of forest that are resistant, persistent or vulnerable to severe drought. The results provide a long-term perspective for the resource management of this area and can be applied to similar ecosystems throughout western North America.

Too-Comfortable Strangers: Cultural Association among the Sephardim of Washington, D.C.

ERIC Educational Resources Information Center

Fredman, Ruth Gruber

The power of the symbol "Sephardic" to foster community association is extremely problematical in the Washington, D.C., context. Washington's Sephardic population is heterogeneous with respect to generation, self-definition, and culture. Complicating the situation is the nature of Washington itself, which in turn is inextricably linked…

British Higher Education and Its Older Clients.

ERIC Educational Resources Information Center

Woodley, Alan; Wilson, Jane

2002-01-01

Using results from a survey of British graduates, examined outcomes of higher education for older students, including their current employment situation, relationship of degree to job, and student satisfaction. Found that mature students are an extremely heterogeneous group, with differences in outcomes by age and mode of study. (EV)

Quantitative experimental monitoring of molecular diffusion in clay with positron emission tomography

NASA Astrophysics Data System (ADS)

Kulenkampff, Johannes; Zakhnini, Abdelhamid; Gründig, Marion; Lippmann-Pipke, Johanna

2016-08-01

Clay plays a prominent role as barrier material in the geosphere. The small particle sizes cause extremely small pore sizes and induce low permeability and high sorption capacity. Transport of dissolved species by molecular diffusion, driven only by a concentration gradient, is less sensitive to the pore size. Heterogeneous structures on the centimetre scale could cause heterogeneous effects, like preferential transport zones, which are difficult to assess. Laboratory measurements with diffusion cells yield limited information on heterogeneity, and pore space imaging methods have to consider scale effects. We established positron emission tomography (PET), applying a high-resolution PET scanner as a spatially resolved quantitative method for direct laboratory observation of the molecular diffusion process of a PET tracer on the prominent scale of 1-100 mm. Although PET is rather insensitive to bulk effects, quantification required significant improvements of the image reconstruction procedure with respect to Compton scatter and attenuation. The experiments were conducted with 22Na and 124I over periods of 100 and 25 days, respectively. From the images we derived trustable anisotropic diffusion coefficients and, in addition, we identified indications of preferential transport zones. We thus demonstrated the unique potential of the PET imaging modality for geoscientific process monitoring under conditions where other methods fail, taking advantage of the extremely high detection sensitivity that is typical of radiotracer applications.

Prostate-specific membrane antigen-directed nanoparticle targeting for extreme nearfield ablation of prostate cancer cells.

PubMed

Lee, Seung S; Roche, Philip Jr; Giannopoulos, Paresa N; Mitmaker, Elliot J; Tamilia, Michael; Paliouras, Miltiadis; Trifiro, Mark A

2017-03-01

Almost all biological therapeutic interventions cannot overcome neoplastic heterogeneity. Physical ablation therapy is immune to tumor heterogeneity, but nearby tissue damage is the limiting factor in delivering lethal doses. Multi-walled carbon nanotubes offer a number of unique properties: chemical stability, photonic properties including efficient light absorption, thermal conductivity, and extensive surface area availability for covalent chemical ligation. When combined together with a targeting moiety such as an antibody or small molecule, one can deliver highly localized temperature increases and cause extensive cellular damage. We have functionalized multi-walled carbon nanotubes by conjugating an antibody against prostate-specific membrane antigen. In our in vitro studies using prostate-specific membrane antigen-positive LNCaP prostate cancer cells, we have effectively demonstrated cell ablation of >80% with a single 30-s exposure to a 2.7-W, 532-nm laser for the first time without bulk heating. We also confirmed the specificity and selectivity of prostate-specific membrane antigen targeting by assessing prostate-specific membrane antigen-null PC3 cell lines under the same conditions (<10% cell ablation). This suggests that we can achieve an extreme nearfield cell ablation effect, thus restricting potential tissue damage when transferred to in vivo clinical applications. Developing this new platform will introduce novel approaches toward current therapeutic modalities and will usher in a new age of effective cancer treatment squarely addressing tumoral heterogeneity.

Gap Junction Coupling and Calcium Waves in the Pancreatic Islet

PubMed Central

Benninger, Richard K. P.; Zhang, Min; Head, W. Steven; Satin, Leslie S.; Piston, David W.

2008-01-01

The pancreatic islet is a highly coupled, multicellular system that exhibits complex spatiotemporal electrical activity in response to elevated glucose levels. The emergent properties of islets, which differ from those arising in isolated islet cells, are believed to arise in part by gap junctional coupling, but the mechanisms through which this coupling occurs are poorly understood. To uncover these mechanisms, we have used both high-speed imaging and theoretical modeling of the electrical activity in pancreatic islets under a reduction in the gap junction mediated electrical coupling. Utilizing islets from a gap junction protein connexin 36 knockout mouse model together with chemical inhibitors, we can modulate the electrical coupling in the islet in a precise manner and quantify this modulation by electrophysiology measurements. We find that after a reduction in electrical coupling, calcium waves are slowed as well as disrupted, and the number of cells showing synchronous calcium oscillations is reduced. This behavior can be reproduced by computational modeling of a heterogeneous population of β-cells with heterogeneous levels of electrical coupling. The resulting quantitative agreement between the data and analytical models of islet connectivity, using only a single free parameter, reveals the mechanistic underpinnings of the multicellular behavior of the islet. PMID:18805925

Application of spatial time domain reflectometry measurements in heterogeneous, rocky substrates

NASA Astrophysics Data System (ADS)

Gonzales, C.; Scheuermann, A.; Arnold, S.; Baumgartl, T.

2016-10-01

Measurement of soil moisture across depths using sensors is currently limited to point measurements or remote sensing technologies. Point measurements have limitations on spatial resolution, while the latter, although covering large areas may not represent real-time hydrologic processes, especially near the surface. The objective of the study was to determine the efficacy of elongated soil moisture probes—spatial time domain reflectometry (STDR)—and to describe transient soil moisture dynamics of unconsolidated mine waste rock materials. The probes were calibrated under controlled conditions in the glasshouse. Transient soil moisture content was measured using the gravimetric method and STDR. Volumetric soil moisture content derived from weighing was compared with values generated from a numerical model simulating the drying process. A calibration function was generated and applied to STDR field data sets. The use of elongated probes effectively assists in the real-time determination of the spatial distribution of soil moisture. It also allows hydrologic processes to be uncovered in the unsaturated zone, especially for water balance calculations that are commonly based on point measurements. The elongated soil moisture probes can potentially describe transient substrate processes and delineate heterogeneity in terms of the pore size distribution in a seasonally wet but otherwise arid environment.

Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia.

PubMed

Giustacchini, Alice; Thongjuea, Supat; Barkas, Nikolaos; Woll, Petter S; Povinelli, Benjamin J; Booth, Christopher A G; Sopp, Paul; Norfo, Ruggiero; Rodriguez-Meira, Alba; Ashley, Neil; Jamieson, Lauren; Vyas, Paresh; Anderson, Kristina; Segerstolpe, Åsa; Qian, Hong; Olsson-Strömberg, Ulla; Mustjoki, Satu; Sandberg, Rickard; Jacobsen, Sten Eirik W; Mead, Adam J

2017-06-01

Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.

Identification and Sensitivity Analysis for Average Causal Mediation Effects with Time-Varying Treatments and Mediators: Investigating the Underlying Mechanisms of Kindergarten Retention Policy.

PubMed

Park, Soojin; Steiner, Peter M; Kaplan, David

2018-06-01

Considering that causal mechanisms unfold over time, it is important to investigate the mechanisms over time, taking into account the time-varying features of treatments and mediators. However, identification of the average causal mediation effect in the presence of time-varying treatments and mediators is often complicated by time-varying confounding. This article aims to provide a novel approach to uncovering causal mechanisms in time-varying treatments and mediators in the presence of time-varying confounding. We provide different strategies for identification and sensitivity analysis under homogeneous and heterogeneous effects. Homogeneous effects are those in which each individual experiences the same effect, and heterogeneous effects are those in which the effects vary over individuals. Most importantly, we provide an alternative definition of average causal mediation effects that evaluates a partial mediation effect; the effect that is mediated by paths other than through an intermediate confounding variable. We argue that this alternative definition allows us to better assess at least a part of the mediated effect and provides meaningful and unique interpretations. A case study using ECLS-K data that evaluates kindergarten retention policy is offered to illustrate our proposed approach.

Characterizing polymorphic inversions in human genomes by single-cell sequencing

PubMed Central

Sanders, Ashley D.; Hills, Mark; Porubský, David; Guryev, Victor; Falconer, Ester; Lansdorp, Peter M.

2016-01-01

Identifying genomic features that differ between individuals and cells can help uncover the functional variants that drive phenotypes and disease susceptibilities. For this, single-cell studies are paramount, as it becomes increasingly clear that the contribution of rare but functional cellular subpopulations is important for disease prognosis, management, and progression. Until now, studying these associations has been challenged by our inability to map structural rearrangements accurately and comprehensively. To overcome this, we coupled single-cell sequencing of DNA template strands (Strand-seq) with custom analysis software to rapidly discover, map, and genotype genomic rearrangements at high resolution. This allowed us to explore the distribution and frequency of inversions in a heterogeneous cell population, identify several polymorphic domains in complex regions of the genome, and locate rare alleles in the reference assembly. We then mapped the entire genomic complement of inversions within two unrelated individuals to characterize their distinct inversion profiles and built a nonredundant global reference of structural rearrangements in the human genome. The work described here provides a powerful new framework to study structural variation and genomic heterogeneity in single-cell samples, whether from individuals for population studies or tissue types for biomarker discovery. PMID:27472961

BASiCS: Bayesian Analysis of Single-Cell Sequencing Data

PubMed Central

Vallejos, Catalina A.; Marioni, John C.; Richardson, Sylvia

2015-01-01

Single-cell mRNA sequencing can uncover novel cell-to-cell heterogeneity in gene expression levels in seemingly homogeneous populations of cells. However, these experiments are prone to high levels of unexplained technical noise, creating new challenges for identifying genes that show genuine heterogeneous expression within the population of cells under study. BASiCS (Bayesian Analysis of Single-Cell Sequencing data) is an integrated Bayesian hierarchical model where: (i) cell-specific normalisation constants are estimated as part of the model parameters, (ii) technical variability is quantified based on spike-in genes that are artificially introduced to each analysed cell’s lysate and (iii) the total variability of the expression counts is decomposed into technical and biological components. BASiCS also provides an intuitive detection criterion for highly (or lowly) variable genes within the population of cells under study. This is formalised by means of tail posterior probabilities associated to high (or low) biological cell-to-cell variance contributions, quantities that can be easily interpreted by users. We demonstrate our method using gene expression measurements from mouse Embryonic Stem Cells. Cross-validation and meaningful enrichment of gene ontology categories within genes classified as highly (or lowly) variable supports the efficacy of our approach. PMID:26107944

BASiCS: Bayesian Analysis of Single-Cell Sequencing Data.

PubMed

Vallejos, Catalina A; Marioni, John C; Richardson, Sylvia

2015-06-01

Single-cell mRNA sequencing can uncover novel cell-to-cell heterogeneity in gene expression levels in seemingly homogeneous populations of cells. However, these experiments are prone to high levels of unexplained technical noise, creating new challenges for identifying genes that show genuine heterogeneous expression within the population of cells under study. BASiCS (Bayesian Analysis of Single-Cell Sequencing data) is an integrated Bayesian hierarchical model where: (i) cell-specific normalisation constants are estimated as part of the model parameters, (ii) technical variability is quantified based on spike-in genes that are artificially introduced to each analysed cell's lysate and (iii) the total variability of the expression counts is decomposed into technical and biological components. BASiCS also provides an intuitive detection criterion for highly (or lowly) variable genes within the population of cells under study. This is formalised by means of tail posterior probabilities associated to high (or low) biological cell-to-cell variance contributions, quantities that can be easily interpreted by users. We demonstrate our method using gene expression measurements from mouse Embryonic Stem Cells. Cross-validation and meaningful enrichment of gene ontology categories within genes classified as highly (or lowly) variable supports the efficacy of our approach.

A novel approach for predicting microRNA-disease associations by unbalanced bi-random walk on heterogeneous network.

PubMed

Luo, Jiawei; Xiao, Qiu

2017-02-01

MicroRNAs (miRNAs) play a critical role by regulating their targets in post-transcriptional level. Identification of potential miRNA-disease associations will aid in deciphering the pathogenesis of human polygenic diseases. Several computational models have been developed to uncover novel miRNA-disease associations based on the predicted target genes. However, due to the insufficient number of experimentally validated miRNA-target interactions as well as the relatively high false-positive and false-negative rates of predicted target genes, it is still challenging for these prediction models to obtain remarkable performances. The purpose of this study is to prioritize miRNA candidates for diseases. We first construct a heterogeneous network, which consists of a disease similarity network, a miRNA functional similarity network and a known miRNA-disease association network. Then, an unbalanced bi-random walk-based algorithm on the heterogeneous network (BRWH) is adopted to discover potential associations by exploiting bipartite subgraphs. Based on 5-fold cross validation, the proposed network-based method achieves AUC values ranging from 0.782 to 0.907 for the 22 human diseases and an average AUC of almost 0.846. The experiments indicated that BRWH can achieve better performances compared with several popular methods. In addition, case studies of some common diseases further demonstrated the superior performance of our proposed method on prioritizing disease-related miRNA candidates. Copyright © 2017 Elsevier Inc. All rights reserved.

Mitochondrial DNA variability among six South American Amerindian villages from the Pano linguistic group.

PubMed

Mendes-Junior, Celso T; Simoes, Aguinaldo L

2014-01-01

Although scattered throughout a large geographic area, the members of the Pano linguistic group present strong ethnic, linguistic, and cultural homogeneity, a feature that causes them to be considered components of a same "Pano" tribe. Nevertheless, the genetic homogeneity between Pano villages has not yet been examined. To study the genetic structure of the Pano linguistic group, four major Native American mitochondrial DNA (mtDNA) founder haplogroups were analyzed in 77 Amerindians from six villages of four Pano tribes (Katukina, Kaxináwa, Marúbo, and Yaminawa) located in the Brazilian Amazon. The central position of these tribes in the continent makes them relevant for attempts to reconstruct population movements in South America. Except for a single individual that presented an African haplogroup L, all remaining individuals presented one of the four Native American haplogroups. Significant heterogeneity was observed across the six Pano villages. Although Amerindian populations are usually characterized by considerable interpopulational diversity, the high heterogeneity level observed is unexpected if the strong ethnic, linguistic, and cultural homogeneity of the Pano linguistic group is taken into account. The present findings indicate that the ethnic, linguistic, and cultural homogeneity does not imply genetic homogeneity. Even though the genetic heterogeneity uncovered may be a female-specific process, the most probable explanation for that is the joint action of isolation and genetic drift as major factors influencing the genetic structure of the Pano linguistic group. Copyright © 2014 Wayne State University Press, Detroit, Michigan 48201-1309.

Scuba: scalable kernel-based gene prioritization.

PubMed

Zampieri, Guido; Tran, Dinh Van; Donini, Michele; Navarin, Nicolò; Aiolli, Fabio; Sperduti, Alessandro; Valle, Giorgio

2018-01-25

The uncovering of genes linked to human diseases is a pressing challenge in molecular biology and precision medicine. This task is often hindered by the large number of candidate genes and by the heterogeneity of the available information. Computational methods for the prioritization of candidate genes can help to cope with these problems. In particular, kernel-based methods are a powerful resource for the integration of heterogeneous biological knowledge, however, their practical implementation is often precluded by their limited scalability. We propose Scuba, a scalable kernel-based method for gene prioritization. It implements a novel multiple kernel learning approach, based on a semi-supervised perspective and on the optimization of the margin distribution. Scuba is optimized to cope with strongly unbalanced settings where known disease genes are few and large scale predictions are required. Importantly, it is able to efficiently deal both with a large amount of candidate genes and with an arbitrary number of data sources. As a direct consequence of scalability, Scuba integrates also a new efficient strategy to select optimal kernel parameters for each data source. We performed cross-validation experiments and simulated a realistic usage setting, showing that Scuba outperforms a wide range of state-of-the-art methods. Scuba achieves state-of-the-art performance and has enhanced scalability compared to existing kernel-based approaches for genomic data. This method can be useful to prioritize candidate genes, particularly when their number is large or when input data is highly heterogeneous. The code is freely available at https://github.com/gzampieri/Scuba .

Single-cell RNA-Seq reveals cell heterogeneity and hierarchy within mouse mammary epithelia.

PubMed

Sun, Heng; Miao, Zhengqiang; Zhang, Xin; Chan, Un In; Su, Sek Man; Guo, Sen; Wong, Chris Koon Ho; Xu, Xiaoling; Deng, Chu-Xia

2018-06-01

The mammary gland is very intricately and well organized into distinct tissues, including epithelia, endothelia, adipocytes, and stromal and immune cells. Many mammary gland diseases, such as breast cancer, arise from abnormalities in the mammary epithelium, which is mainly composed of two distinct lineages, the basal and luminal cells. Because of the limitation of traditional transcriptome analysis of bulk mammary cells, the hierarchy and heterogeneity of mammary cells within these two lineages remain unclear. To this end, using single-cell RNA-Seq coupled with FACS analysis and principal component analysis, we determined gene expression profiles of mammary epithelial cells of virgin and pregnant mice. These analyses revealed a much higher heterogeneity among the mammary cells than has been previously reported and enabled cell classification into distinct subgroups according to signature gene markers present in each group. We also identified and verified a rare CDH5 + cell subpopulation within a basal cell lineage as quiescent mammary stem cells (MaSCs). Moreover, using pseudo-temporal analysis, we reconstructed the developmental trajectory of mammary epithelia and uncovered distinct changes in gene expression and in biological functions of mammary cells along the developmental process. In conclusion, our work greatly refines the resolution of the cellular hierarchy in developing mammary tissues. The discovery of CDH5 + cells as MaSCs in these tissues may have implications for our understanding of the initiation, development, and pathogenesis of mammary tumors. © 2018 Sun et al.

Recovery of upper limb muscle function in chronic fatigue syndrome with and without fibromyalgia.

PubMed

Ickmans, Kelly; Meeus, Mira; De Kooning, Margot; Lambrecht, Luc; Nijs, Jo

2014-02-01

Chronic fatigue syndrome (CFS) patients frequently complain of muscle fatigue and abnormally slow recovery, especially of the upper limb muscles during and after activities of daily living. Furthermore, disease heterogeneity has not yet been studied in relation to recovery of muscle function in CFS. Here, we examine recovery of upper limb muscle function from a fatiguing exercise in CFS patients with (CFS+FM) and without (CFS-only) comorbid fibromyalgia and compare their results with a matched inactive control group. In this case-control study, 18 CFS-only patients, 30 CFS+FM patients and 30 healthy inactive controls performed a fatiguing upper limb exercise test with subsequent recovery measures. There was no significant difference among the three groups for maximal handgrip strength of the non-dominant hand. A significant worse recovery of upper limb muscle function was found in the CFS+FM, but not in de CFS-only group compared with the controls (P < 0·05). This study reveals, for the first time, delayed recovery of upper limb muscle function in CFS+FM, but not in CFS-only patients. The results underline that CFS is a heterogeneous disorder suggesting that reducing the heterogeneity of the disorder in future research is important to make progress towards a better understanding and uncovering of mechanisms regarding the nature of divers impairments in these patients. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

Are Press Depictions of Affordable Care Act Beneficiaries Favorable to Policy Durability?

PubMed

Chattopadhyay, Jacqueline

2015-01-01

If successfully implemented and enduring, the Affordable Care Act (ACA) stands to expand health insurance access in absolute terms, reduce inter-group disparities in that access, and reduce exposure to the financial vulnerabilities illness entails. Its durability--meaning both avoidance of outright retrenchment and fidelity to its policy aims--is thus of scholarly interest. Past literature suggests that social constructions of a policy's beneficiaries may impact durability. This paper first describes media portrayals of ACA beneficiaries with an eye toward answering three descriptive questions: (1) Do portrayals depict beneficiaries as economically heterogeneous? (2) Do portrayals focus attention on groups that have acquired new political relevance due to the ACA, such as young adults? (3) What themes that have served as messages about beneficiary "deservingness" in past social policy are most frequent in ACA beneficiary portrayals? The paper then assesses how the portrayal patterns that these questions uncover may work both for and against the ACA's durability, finding reasons for confidence as well as caution. Using manual and automated methods, this paper analyzes newspaper text from August 2013 through January 2014 to trace portrayals of two ACA "target populations" before and during the new law's first open-enrollment period: those newly eligible for Medicaid, and those eligible for subsidies to assist in the purchase of private health insurance under the ACA. This paper also studies newspaper text portrayals of two groups informally crafted by the ACA in this timeframe: those gaining health insurance and those losing it. The text data uncover the following answers to the three descriptive questions for the timeframe studied: (1) Portrayals may underplay beneficiaries' economic heterogeneity. (2) Portrayals pay little attention to young adults. (3) Portrayals emphasize themes of workforce participation, economic self-sufficiency, and insider status. Health status, age, gender, and race/ethnicity appear to receive little attention. Existing literature suggests that these portrayal patterns may both support and limit ACA durability. In favor of durability is that ACA beneficiaries are depicted in terms that have been associated with deservingness in past American social policy--particularly being cast as workers and insiders. Yet, the results also give three reasons for caution. First, ACA insurance-losers are also portrayed as deserving. Second, it is unclear how the portrayal patterns found may impact the durability of the ACA's efforts to cut insurance disparities by age, health status, and especially race/ethnicity. Third, portrayals' strong casting of beneficiaries as workers, and limited attention to beneficiaries' economic heterogeneity and to young adults, may do little to help cultivate beneficiary political engagement around the ACA.

Quinto Tiberio Angelerio and New Measures for Controlling Plague in 16th-Century Alghero, Sardinia

PubMed Central

Benedictow, Ole Jørgen; Fornaciari, Gino; Giuffra, Valentina

2013-01-01

Plague, a zoonotic disease caused by the bacterium Yersinia pestis, has been responsible for at least 3 pandemics. During 1582–1583, a plague outbreak devastated the seaport of Alghero in Sardinia. By analyzing contemporary medical texts and local documentation, we uncovered the pivotal role played by the Protomedicus of Alghero, Quinto Tiberio Angelerio (1532–1617), in controlling the epidemic. Angelerio imposed rules and antiepidemic measures new to the 16th-century sanitary system of Sardinia. Those measures undoubtedly spared the surrounding districts from the spread of the contagion. Angelerio seems to have been an extremely successful public health officer in the history of plague epidemics in Sardinia. PMID:23968598

Visible Machine Learning for Biomedicine.

PubMed

Yu, Michael K; Ma, Jianzhu; Fisher, Jasmin; Kreisberg, Jason F; Raphael, Benjamin J; Ideker, Trey

2018-06-14

A major ambition of artificial intelligence lies in translating patient data to successful therapies. Machine learning models face particular challenges in biomedicine, however, including handling of extreme data heterogeneity and lack of mechanistic insight into predictions. Here, we argue for "visible" approaches that guide model structure with experimental biology. Copyright © 2018. Published by Elsevier Inc.

Unpacking "Active Learning": A Combination of Flipped Classroom and Collaboration Support Is More Effective but Collaboration Support Alone Is Not

ERIC Educational Resources Information Center

Rau, Martina A.; Kennedy, Kristopher; Oxtoby, Lucas; Bollom, Mark; Moore, John W.

2017-01-01

Much evidence shows that instruction that actively engages students with learning materials is more effective than traditional, lecture-centric instruction. These "active learning" models comprise an extremely heterogeneous set of instructional methods: they often include collaborative activities, flipped classrooms, or a combination of…

An exploratory comparison of name generator content: Data from rural India

PubMed Central

Shakya, Holly B.; Christakis, Nicholas A.; Fowler, James H.

2017-01-01

Since the 1970s sociologists have explored the best means for measuring social networks, although few name generator analyses have used sociocentric data or data from developing countries, partly because sociocentric studies in developing countries have been scant. Here, we analyze 12 different name generators used in a sociocentric network study conducted in 75 villages in rural Karnataka, India. Having unusual sociocentric data from a non-Western context allowed us to extend previous name generator research through the unique analyses of network structural measures, an extensive consideration of homophily, and investigation of status difference between egos and alters. We found that domestic interaction questions generated networks that were highly clustered and highly centralized. Similarity between respondents and their nominated contacts was strongest for gender, caste, and religion. We also found that domestic interaction name generators yielded the most homogeneous ties, while advice questions yielded the most heterogeneous. Participants were generally more likely to nominate those of higher social status, although certain questions, such as who participants talk to uncovered more egalitarian relationships, while other name generators elicited the names of social contacts distinctly higher or lower in status than the respondent. Some questions also seemed to uncover networks that were specific to the cultural context, suggesting that network researchers should balance local relevance with global generalizability when choosing name generators. PMID:28845086

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-05-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-04-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias

PubMed Central

Morais, Sara; Raymond, Laure; Mairey, Mathilde; Coutinho, Paula; Brandão, Eva; Ribeiro, Paula; Loureiro, José Leal; Sequeiros, Jorge; Brice, Alexis; Alonso, Isabel; Stevanin, Giovanni

2017-01-01

Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (>60 causative genes), 40–70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes. We identified the likely disease-causing variant in 20 of the 98 families with KIF5A being the most frequently mutated gene. We also found 52 variants of unknown significance (VUS) in 38% of the cases. These new diagnoses resulted in 42% of solved cases in the full Portuguese cohort (81/193). Segregation of the variants was not always compatible with the presumed inheritance, indicating that the analysis of all HSP genes regardless of the inheritance mode can help to explain some cases. Our results show that there is still a large set of unknown genes responsible for HSP and most likely novel mechanisms or inheritance modes leading to the disease to be uncovered, but this will require international collaborative efforts, particularly for the analysis of VUS. PMID:28832565

Genetic heterogeneity in autism: From single gene to a pathway perspective.

PubMed

An, Joon Yong; Claudianos, Charles

2016-09-01

The extreme genetic heterogeneity of autism spectrum disorder (ASD) represents a major challenge. Recent advances in genetic screening and systems biology approaches have extended our knowledge of the genetic etiology of ASD. In this review, we discuss the paradigm shift from a single gene causation model to pathway perturbation model as a guide to better understand the pathophysiology of ASD. We discuss recent genetic findings obtained through next-generation sequencing (NGS) and examine various integrative analyses using systems biology and complex networks approaches that identify convergent patterns of genetic elements associated with ASD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Complex genetics of familial exudative vitreoretinopathy and related pediatric retinal detachments

PubMed Central

Kondo, Hiroyuki

2015-01-01

Familial exudative vitreoretinopathy (FEVR) is a hereditary vitreoretinal disorder that can cause various types of retinal detachments. The abnormalities in eyes with FEVR are caused by poor vascularization in the peripheral retina. The genetics of FEVR is highly heterogeneous, and mutations in the genes for Wnt signaling and a transcription factor have been reported to be responsible for FEVR. These factors have been shown to be the regulators of the pathophysiological pathways of retinal vascular development. Studies conducted to identify the causative genes of FEVR have uncovered a diverse and complex relationship between FEVR and other diseases; for example, Norrie disease, a Mendelian-inherited disease; retinopathy of prematurity, a multifactorial genetic disease; and Coats disease, a nongenetic disease, associated with pediatric retinal detachments. PMID:29018668

Identifying women with dense breasts at high risk for interval cancer: a cohort study.

PubMed

Kerlikowske, Karla; Zhu, Weiwei; Tosteson, Anna N A; Sprague, Brian L; Tice, Jeffrey A; Lehman, Constance D; Miglioretti, Diana L

2015-05-19

Twenty-one states have laws requiring that women be notified if they have dense breasts and that they be advised to discuss supplemental imaging with their provider. To better direct discussions of supplemental imaging by determining which combinations of breast cancer risk and Breast Imaging Reporting and Data System (BI-RADS) breast density categories are associated with high interval cancer rates. Prospective cohort. Breast Cancer Surveillance Consortium (BCSC) breast imaging facilities. 365,426 women aged 40 to 74 years who had 831,455 digital screening mammography examinations. BI-RADS breast density, BCSC 5-year breast cancer risk, and interval cancer rate (invasive cancer ≤12 months after a normal mammography result) per 1000 mammography examinations. High interval cancer rate was defined as more than 1 case per 1000 examinations. High interval cancer rates were observed for women with 5-year risk of 1.67% or greater and extremely dense breasts or 5-year risk of 2.50% or greater and heterogeneously dense breasts (24% of all women with dense breasts). The interval rate of advanced-stage disease was highest (>0.4 case per 1000 examinations) among women with 5-year risk of 2.50% or greater and heterogeneously or extremely dense breasts (21% of all women with dense breasts). Five-year risk was low to average (0% to 1.66%) for 51.0% of women with heterogeneously dense breasts and 52.5% with extremely dense breasts, with interval cancer rates of 0.58 to 0.63 and 0.72 to 0.89 case per 1000 examinations, respectively. The benefit of supplemental imaging was not assessed. Breast density should not be the sole criterion for deciding whether supplemental imaging is justified because not all women with dense breasts have high interval cancer rates. BCSC 5-year risk combined with BI-RADS breast density can identify women at high risk for interval cancer to inform patient-provider discussions about alternative screening strategies. National Cancer Institute.

A case of idiopathic type 1 diabetes with subsequent recovery of endogenous insulin secretion despite initial diagnosis of fulminant type 1 diabetes.

PubMed

Kaneko, Keizo; Satake, Chihiro; Yamamoto, Junpei; Takahashi, Hironori; Sawada, Shojiro; Imai, Junta; Yamada, Tetsuya; Katagiri, Hideki

2017-03-31

Fulminant type 1 diabetes is characterized by remarkably rapid and complete β-cell destruction. The established diagnostic criteria include the occurrence of diabetic ketosis soon after the onset of hyperglycemic symptoms, elevated plasma glucose with relatively low HbA1c at the first visit, and extremely low C-peptide. Serum C-peptide levels remain extremely low over a prolonged period. A 26-year-old-man with diabetic ketosis was admitted to our hospital. His relatively low HbA1c (7.6%), despite marked hyperglycemia (593 mg/dL) with marked ketosis, indicated abrupt onset. Islet-related autoantibodies were all negative. His data at onset, including extremely low serum C-peptide (0.11 ng/mL), fulfilled the diagnostic criteria for fulminant type 1 diabetes. However, his fasting serum C-peptide levels subsequently showed substantial recovery. While fasting C-peptide stayed below 0.30 ng/mL during the first two months post onset, the levels gradually increased and thereafter fluctuated between 0.60 ng/mL and 0.90 ng/mL until 24 months post onset. By means of multiple daily insulin injection therapy, his glycemic control has been well maintained (HbA1c approximately 6.0%), with relatively small glycemic fluctuations evaluated by continuous glucose monitoring. This clinical course suggests that, despite the abrupt diabetes onset with extremely low C-peptide levels, substantial numbers of β-cells had been spared destruction and their function later showed gradual recovery. Diabetes has come to be considered a much more heterogeneous disease than the present subdivisions suggest. This case does not fit into the existing concepts of either fulminant type 1 or ketosis-prone diabetes, thereby further highlighting the heterogeneity of idiopathic type 1 diabetes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bramante, Joseph; Linden, Tim

Recent observations of Reticulum II have uncovered an overabundance of r -process elements compared to similar ultra-faint dwarf spheroidal galaxies (UFDs). Because the metallicity and star formation history of Reticulum II appear consistent with all known UFDs, the high r -process abundance of Reticulum II suggests enrichment through a single, rare event, such as a double neutron star (NS) merger. However, we note that this scenario is extremely unlikely, as binary stellar evolution models require significant supernova natal kicks to produce NS–NS or NS–black hole (BH) mergers, and these kicks would efficiently remove compact binary systems from the weak gravitationalmore » potentials of UFDs. We examine alternative mechanisms for the production of r -process elements in UFDs, including a novel mechanism wherein NSs in regions of high dark matter (DM) density implode after accumulating a BH-forming mass of DM. We find that r -process proto-material ejection by tidal forces, when a single NS implodes into a BH, can occur at a rate matching the r -process abundance of both Reticulum II and the Milky Way. Remarkably, DM models which collapse a single NS in observed UFDs also solve the missing pulsar problem in the Milky Way Galactic Center. We propose tests specific to DM r -process production which may uncover or rule out this model.« less

Uncovering the repertoire of fungal secondary metabolites: From Fleming's laboratory to the International Space Station.

PubMed

Boruta, Tomasz

2018-01-01

Fungi produce a variety of secondary metabolites (SMs), low-molecular weight compounds associated with many potentially useful biologic activities. The examples of biotechnologically relevant fungal metabolites include penicillin, a β-lactam antibiotic, and lovastatin, a cholesterol-lowering drug. The discovery of pharmaceutical lead compounds within the microbial metabolic pools relies on the selection and biochemical characterization of promising strains. Not all SMs are produced under standard cultivation conditions, hence the uncovering of chemical potential of investigated strains often requires the use of induction strategies to awake the associated biosynthetic genes. Triggering the secondary metabolic pathways can be achieved through the variation of cultivation conditions and growth media composition. The alternative strategy is to use genetic engineering to activate the respective genomic segments, e.g. by the manipulation of regulators or chromatin-modifying enzymes. Recently, whole-genome sequencing of several fungi isolated from the Chernobyl accident area was reported by Singh et al. (Genome Announc 2017; 5:e01602-16). These strains were selected for exposure to microgravity at the International Space Station. Biochemical characterization of fungi cultivated under extreme conditions is likely to provide valuable insights into the adaptation mechanism associated with metabolism and, possibly, a catalog of novel molecules of potential pharmaceutical importance.

Projected timing of perceivable changes in climate extremes for terrestrial and marine ecosystems.

PubMed

Tan, Xuezhi; Gan, Thian Yew; Horton, Daniel E

2018-05-26

Human and natural systems have adapted to and evolved within historical climatic conditions. Anthropogenic climate change has the potential to alter these conditions such that onset of unprecedented climatic extremes will outpace evolutionary and adaptive capabilities. To assess whether and when future climate extremes exceed their historical windows of variability within impact-relevant socioeconomic, geopolitical, and ecological domains, we investigate the timing of perceivable changes (time of emergence; TOE) for 18 magnitude-, frequency-, and severity-based extreme temperature (10) and precipitation (8) indices using both multimodel and single-model multirealization ensembles. Under a high-emission scenario, we find that the signal of frequency- and severity-based temperature extremes is projected to rise above historical noise earliest in midlatitudes, whereas magnitude-based temperature extremes emerge first in low and high latitudes. Precipitation extremes demonstrate different emergence patterns, with severity-based indices first emerging over midlatitudes, and magnitude- and frequency-based indices emerging earliest in low and high latitudes. Applied to impact-relevant domains, simulated TOE patterns suggest (a) unprecedented consecutive dry day occurrence in >50% of 14 terrestrial biomes and 12 marine realms prior to 2100, (b) earlier perceivable changes in climate extremes in countries with lower per capita GDP, and (c) emergence of severe and frequent heat extremes well-before 2030 for the 590 most populous urban centers. Elucidating extreme-metric and domain-type TOE heterogeneities highlights the challenges adaptation planners face in confronting the consequences of elevated twenty-first century radiative forcing. © 2018 John Wiley & Sons Ltd.

A monograph proposing the use of canine mammary tumours as a model for the study of hereditary breast cancer susceptibility genes in humans.

PubMed

Goebel, Katie; Merner, Nancy D

2017-05-01

Canines are excellent models for cancer studies due to their similar physiology and genomic sequence to humans, companion status and limited intra-breed heterogeneity. Due to their affliction to mammary cancers, canines can serve as powerful genetic models of hereditary breast cancers. Variants within known human breast cancer susceptibility genes only explain a fraction of familial cases. Thus, further discovery is necessary but such efforts have been thwarted by genetic heterogeneity. Reducing heterogeneity is key, and studying isolated human populations have helped in the endeavour. An alternative is to study dog pedigrees, since artificial selection has resulted in extreme homogeneity. Identifying the genetic predisposition to canine mammary tumours can translate to human discoveries - a strategy currently underutilized. To explore this potential, we reviewed published canine mammary tumour genetic studies and proposed benefits of next generation sequencing canine cohorts to facilitate moving beyond incremental advances.

Teamwork and collaboration in long-duration space missions: Going to extremes.

PubMed

Landon, Lauren Blackwell; Slack, Kelley J; Barrett, Jamie D

2018-01-01

The scientific study of teamwork in the context of spaceflight has uncovered a considerable amount of knowledge over the past 20 years. Although much is known about the underlying factors and processes of teamwork, much is left to be discovered for teams who will be operating in extreme isolation and confinement during a future Mars mission. Special considerations must be made to enhance teamwork and team well-being for multi-year missions during which the small team will live and work together. We discuss the unique challenges of effective teamwork in a Mars mission scenario, and the difficulties of studying teamwork using analogs of the space environment. We then describe the National Aeronautics and Space Administration's current practices and research on teamwork, which includes team selection and composition, teamwork training, countermeasures to mitigate risks to effective team performance, and the measurement and monitoring of team functioning. We end with a discussion of the teamwork research areas that are most critical for a successful journey to Mars. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Probing the character of ultra-fast dislocations

DOE PAGES

Rudd, R. E.; Ruestes, C. J.; Bringa, E. M.; ...

2015-11-23

Plasticity is often controlled by dislocation motion, which was first measured for low pressure, low strain rate conditions decades ago. However, many applications require knowledge of dislocation motion at high stress conditions where the data are sparse, and come from indirect measurements dominated by the effect of dislocation density rather than velocity. Here we make predictions based on atomistic simulations that form the basis for a new approach to measure dislocation velocities directly at extreme conditions using three steps: create prismatic dislocation loops in a near-surface region using nanoindentation, drive the dislocations with a shockwave, and use electron microscopy tomore » determine how far the dislocations moved and thus their velocity at extreme stress and strain rate conditions. We report on atomistic simulations of tantalum that make detailed predictions of dislocation flow, and find that the approach is feasible and can uncover an exciting range of phenomena, such as transonic dislocations and a novel form of loop stretching. Furthermore, the simulated configuration enables a new class of experiments to probe average dislocation velocity at very high applied shear stress.« less

Heterogeneous chemistry: a mechanism missing in current models to explain secondary inorganic aerosol formation during the January 2013 haze episode in North China

DOE PAGES

Zheng, B.; Zhang, Q.; Zhang, Y.; ...

2015-02-25

Severe regional haze pollution events occurred in eastern and central China in January 2013, which had adverse effects on the environment and public health. Extremely high levels of particulate matter with aerodynamic diameter of 2.5 μm or less (PM 2.5) with dominant components of sulfate and nitrate are responsible for the haze pollution. Although heterogeneous chemistry is thought to play an important role in the production of sulfate and nitrate during haze episodes, few studies have comprehensively evaluated the effect of heterogeneous chemistry on haze formation in China by using the 3-D models due to of a lack of treatmentsmore » for heterogeneous reactions in most climate and chemical transport models. In this work, the WRF-CMAQ model with newly added heterogeneous reactions is applied to East Asia to evaluate the impacts of heterogeneous chemistry and the meteorological anomaly during January 2013 on regional haze formation. As the parameterization of heterogeneous reactions on different types of particles is not well established yet, we arbitrarily selected the uptake coefficients from reactions on dust particles and then conducted several sensitivity runs to find the value that can best match observations. The revised CMAQ with heterogeneous chemistry not only captures the magnitude and temporal variation of sulfate and nitrate, but also reproduces the enhancement of relative contribution of sulfate and nitrate to PM 2.5 mass from clean days to polluted haze days. Finally, these results indicate the significant role of heterogeneous chemistry in regional haze formation and improve the understanding of the haze formation mechanisms during the January 2013 episode.« less

Characterizing optical properties and spatial heterogeneity of human ovarian tissue using spatial frequency domain imaging

NASA Astrophysics Data System (ADS)

Nandy, Sreyankar; Mostafa, Atahar; Kumavor, Patrick D.; Sanders, Melinda; Brewer, Molly; Zhu, Quing

2016-10-01

A spatial frequency domain imaging (SFDI) system was developed for characterizing ex vivo human ovarian tissue using wide-field absorption and scattering properties and their spatial heterogeneities. Based on the observed differences between absorption and scattering images of different ovarian tissue groups, six parameters were quantitatively extracted. These are the mean absorption and scattering, spatial heterogeneities of both absorption and scattering maps measured by a standard deviation, and a fitting error of a Gaussian model fitted to normalized mean Radon transform of the absorption and scattering maps. A logistic regression model was used for classification of malignant and normal ovarian tissues. A sensitivity of 95%, specificity of 100%, and area under the curve of 0.98 were obtained using six parameters extracted from the SFDI images. The preliminary results demonstrate the diagnostic potential of the SFDI method for quantitative characterization of wide-field optical properties and the spatial distribution heterogeneity of human ovarian tissue. SFDI could be an extremely robust and valuable tool for evaluation of the ovary and detection of neoplastic changes of ovarian cancer.

Higher rates of sex evolve in spatially heterogeneous environments.

PubMed

Becks, Lutz; Agrawal, Aneil F

2010-11-04

The evolution and maintenance of sexual reproduction has puzzled biologists for decades. Although this field is rich in hypotheses, experimental evidence is scarce. Some important experiments have demonstrated differences in evolutionary rates between sexual and asexual populations; other experiments have documented evolutionary changes in phenomena related to genetic mixing, such as recombination and selfing. However, direct experiments of the evolution of sex within populations are extremely rare (but see ref. 12). Here we use the rotifer, Brachionus calyciflorus, which is capable of both sexual and asexual reproduction, to test recent theory predicting that there is more opportunity for sex to evolve in spatially heterogeneous environments. Replicated experimental populations of rotifers were maintained in homogeneous environments, composed of either high- or low-quality food habitats, or in heterogeneous environments that consisted of a mix of the two habitats. For populations maintained in either type of homogeneous environment, the rate of sex evolves rapidly towards zero. In contrast, higher rates of sex evolve in populations experiencing spatially heterogeneous environments. The data indicate that the higher level of sex observed under heterogeneity is not due to sex being less costly or selection against sex being less efficient; rather sex is sufficiently advantageous in heterogeneous environments to overwhelm its inherent costs. Counter to some alternative theories for the evolution of sex, there is no evidence that genetic drift plays any part in the evolution of sex in these populations.

Adsorption of binary gas mixtures in heterogeneous carbon predicted by density functional theory: on the formation of adsorption azeotropes.

PubMed

Ritter, James A; Pan, Huanhua; Balbuena, Perla B

2010-09-07

Classical density functional theory (DFT) was used to predict the adsorption of nine different binary gas mixtures in a heterogeneous BPL activated carbon with a known pore size distribution (PSD) and in single, homogeneous, slit-shaped carbon pores of different sizes. By comparing the heterogeneous results with those obtained from the ideal adsorbed solution theory and with those obtained in the homogeneous carbon, it was determined that adsorption nonideality and adsorption azeotropes are caused by the coupled effects of differences in the molecular size of the components in a gas mixture and only slight differences in the pore sizes of a heterogeneous adsorbent. For many binary gas mixtures, selectivity was found to be a strong function of pore size. As the width of a homogeneous pore increases slightly, the selectivity for two different sized adsorbates may change from being greater than unity to less than unity. This change in selectivity can be accompanied by the formation of an adsorption azeotrope when this same binary mixture is adsorbed in a heterogeneous adsorbent with a PSD, like in BPL activated carbon. These results also showed that the selectivity exhibited by a heterogeneous adsorbent can be dominated by a small number of pores that are very selective toward one of the components in the gas mixture, leading to adsorption azeotrope formation in extreme cases.

Realism without truth: a review of Giere's science without laws and scientific perspectivism.

PubMed

Hackenberg, Timothy D

2009-05-01

An increasingly popular view among philosophers of science is that of science as action-as the collective activity of scientists working in socially-coordinated communities. Scientists are seen not as dispassionate pursuers of Truth, but as active participants in a social enterprise, and science is viewed on a continuum with other human activities. When taken to an extreme, the science-as-social-process view can be taken to imply that science is no different from any other human activity, and therefore can make no privileged claims about its knowledge of the world. Such extreme views are normally contrasted with equally extreme views of classical science, as uncovering Universal Truth. In Science Without Laws and Scientific Perspectivism, Giere outlines an approach to understanding science that finds a middle ground between these extremes. He acknowledges that science occurs in a social and historical context, and that scientific models are constructions designed and created to serve human ends. At the same time, however, scientific models correspond to parts of the world in ways that can legitimately be termed objective. Giere's position, perspectival realism, shares important common ground with Skinner's writings on science, some of which are explored in this review. Perhaps most fundamentally, Giere shares with Skinner the view that science itself is amenable to scientific inquiry: scientific principles can and should be brought to bear on the process of science. The two approaches offer different but complementary perspectives on the nature of science, both of which are needed in a comprehensive understanding of science.

REALISM WITHOUT TRUTH: A REVIEW OF GIERE'S SCIENCE WITHOUT LAWS AND SCIENTIFIC PERSPECTIVISM

PubMed Central

Hackenberg, Timothy D

2009-01-01

An increasingly popular view among philosophers of science is that of science as action—as the collective activity of scientists working in socially-coordinated communities. Scientists are seen not as dispassionate pursuers of Truth, but as active participants in a social enterprise, and science is viewed on a continuum with other human activities. When taken to an extreme, the science-as-social-process view can be taken to imply that science is no different from any other human activity, and therefore can make no privileged claims about its knowledge of the world. Such extreme views are normally contrasted with equally extreme views of classical science, as uncovering Universal Truth. In Science Without Laws and Scientific Perspectivism, Giere outlines an approach to understanding science that finds a middle ground between these extremes. He acknowledges that science occurs in a social and historical context, and that scientific models are constructions designed and created to serve human ends. At the same time, however, scientific models correspond to parts of the world in ways that can legitimately be termed objective. Giere's position, perspectival realism, shares important common ground with Skinner's writings on science, some of which are explored in this review. Perhaps most fundamentally, Giere shares with Skinner the view that science itself is amenable to scientific inquiry: scientific principles can and should be brought to bear on the process of science. The two approaches offer different but complementary perspectives on the nature of science, both of which are needed in a comprehensive understanding of science. PMID:19949495

Extensive de novo mutation rate variation between individuals and across the genome of Chlamydomonas reinhardtii

PubMed Central

Ness, Rob W.; Morgan, Andrew D.; Vasanthakrishnan, Radhakrishnan B.; Colegrave, Nick; Keightley, Peter D.

2015-01-01

Describing the process of spontaneous mutation is fundamental for understanding the genetic basis of disease, the threat posed by declining population size in conservation biology, and much of evolutionary biology. Directly studying spontaneous mutation has been difficult, however, because new mutations are rare. Mutation accumulation (MA) experiments overcome this by allowing mutations to build up over many generations in the near absence of natural selection. Here, we sequenced the genomes of 85 MA lines derived from six genetically diverse strains of the green alga Chlamydomonas reinhardtii. We identified 6843 new mutations, more than any other study of spontaneous mutation. We observed sevenfold variation in the mutation rate among strains and that mutator genotypes arose, increasing the mutation rate approximately eightfold in some replicates. We also found evidence for fine-scale heterogeneity in the mutation rate, with certain sequence motifs mutating at much higher rates, and clusters of multiple mutations occurring at closely linked sites. There was little evidence, however, for mutation rate heterogeneity between chromosomes or over large genomic regions of 200 kbp. We generated a predictive model of the mutability of sites based on their genomic properties, including local GC content, gene expression level, and local sequence context. Our model accurately predicted the average mutation rate and natural levels of genetic diversity of sites across the genome. Notably, trinucleotides vary 17-fold in rate between the most and least mutable sites. Our results uncover a rich heterogeneity in the process of spontaneous mutation both among individuals and across the genome. PMID:26260971

Black Hole Safari: Tracking Populations and Hunting Big Game

NASA Astrophysics Data System (ADS)

McConnell, N. J.

2013-10-01

Understanding the physical connection, or lack thereof, between the growth of galaxies and supermassive black holes is a key challenge in extragalactic astronomy. Dynamical studies of nearby galaxies are building a census of black hole masses across a broad range of galaxy types and uncovering statistical correlations between galaxy bulge properties and black hole masses. These local correlations provide a baseline for studying galaxies and black holes at higher redshifts. Recent measurements have probed the extremes of the supermassive black hole population and introduced surprises that challenge simple models of black hole and galaxy co-evolution. Future advances in the quality and quantity of dynamical black hole mass measurements will shed light upon the growth of massive galaxies and black holes in different cosmic environments.

The Fanconi Anemia Pathway in Replication Stress and DNA Crosslink Repair

PubMed Central

Jones, Mathew JK.; Huang, Tony T.

2013-01-01

Interstand crosslinks (ICLs) are DNA lesions where the bases of opposing DNA strands are covalently linked, inhibiting critical cellular processes such as transcription and replication. Chemical agents that generate ICLs cause chromosomal abnormalities including breaks, deletions and rearrangements, making them highly genotoxic compounds. This toxicity has proven useful for chemotherapeutic treatment against a wide variety of cancer types. The majority of our understanding of ICL repair in humans has been uncovered thorough analysis of the rare genetic disorder Fanconi anemia, in which patients are extremely sensitive to crosslinking agents. Here, we discuss recent insights into ICL repair gained through new ICL repair assays and highlight the role of the Fanconi Anemia repair pathway during replication stress. PMID:22744751

Measuring information interactions on the ordinal pattern of stock time series

NASA Astrophysics Data System (ADS)

Zhao, Xiaojun; Shang, Pengjian; Wang, Jing

2013-02-01

The interactions among time series as individual components of complex systems can be quantified by measuring to what extent they exchange information among each other. In many applications, one focuses not on the original series but on its ordinal pattern. In such cases, trivial noises appear more likely to be filtered and the abrupt influence of extreme values can be weakened. Cross-sample entropy and inner composition alignment have been introduced as prominent methods to estimate the information interactions of complex systems. In this paper, we modify both methods to detect the interactions among the ordinal pattern of stock return and volatility series, and we try to uncover the information exchanges across sectors in Chinese stock markets.

Credit risk and the instability of the financial system: An ensemble approach

NASA Astrophysics Data System (ADS)

Schmitt, Thilo A.; Chetalova, Desislava; Schäfer, Rudi; Guhr, Thomas

2014-02-01

The instability of the financial system as experienced in recent years and in previous periods is often linked to credit defaults, i.e., to the failure of obligors to make promised payments. Given the large number of credit contracts, this problem is amenable to be treated with approaches developed in statistical physics. We introduce the idea of ensemble averaging and thereby uncover generic features of credit risk. We then show that the often advertised concept of diversification, i.e., reducing the risk by distributing it, is deeply flawed when it comes to credit risk. The risk of extreme losses remains due to the ever present correlations, implying a substantial and persistent intrinsic danger to the financial system.

Coldest Temperature Extreme Monotonically Increased and Hottest Extreme Oscillated over Northern Hemisphere Land during Last 114 Years.

PubMed

Zhou, Chunlüe; Wang, Kaicun

2016-05-13

Most studies on global warming rely on global mean surface temperature, whose change is jointly determined by anthropogenic greenhouse gases (GHGs) and natural variability. This introduces a heated debate on whether there is a recent warming hiatus and what caused the hiatus. Here, we presented a novel method and applied it to a 5° × 5° grid of Northern Hemisphere land for the period 1900 to 2013. Our results show that the coldest 5% of minimum temperature anomalies (the coldest deviation) have increased monotonically by 0.22 °C/decade, which reflects well the elevated anthropogenic GHG effect. The warmest 5% of maximum temperature anomalies (the warmest deviation), however, display a significant oscillation following the Atlantic Multidecadal Oscillation (AMO), with a warming rate of 0.07 °C/decade from 1900 to 2013. The warmest (0.34 °C/decade) and coldest deviations (0.25 °C/decade) increased at much higher rates over the most recent decade than last century mean values, indicating the hiatus should not be interpreted as a general slowing of climate change. The significant oscillation of the warmest deviation provides an extension of previous study reporting no pause in the hottest temperature extremes since 1979, and first uncovers its increase from 1900 to 1939 and decrease from 1940 to 1969.

Complex Networks Dynamics Based on Events-Phase Synchronization and Intensity Correlation Applied to The Anomaly Patterns and Extremes in The Tropical African Climate System

NASA Astrophysics Data System (ADS)

Oluoch, K.; Marwan, N.; Trauth, M.; Loew, A.; Kurths, J.

2012-04-01

The African continent lie almost entirely within the tropics and as such its (tropical) climate systems are predominantly governed by the heterogeneous, spatial and temporal variability of the Hadley and Walker circulations. The variabilities in these meridional and zonal circulations lead to intensification or suppression of the intensities, durations and frequencies of the Inter-tropical Convergence Zone (ICTZ) migration, trade winds and subtropical high-pressure regions and the continental monsoons. The above features play a central role in determining the African rainfall spatial and temporal variability patterns. The current understanding of these climate features and their influence on the rainfall patterns is not sufficiently understood. Like many real-world systems, atmospheric-oceanic processes exhibit non-linear properties that can be better explored using non-linear (NL) methods of time-series analysis. Over the recent years, the complex network approach has evolved as a powerful new player in understanding spatio-temporal dynamics and evolution of complex systems. Together with NL techniques, it is continuing to find new applications in many areas of science and technology including climate research. We would like to use these two powerful methods to understand the spatial structure and dynamics of African rainfall anomaly patterns and extremes. The method of event synchronization (ES) developed by Quiroga et al., 2002 and first applied to climate networks by Malik et al., 2011 looks at correlations with a dynamic time lag and as such, it is a more intuitive way to correlate a complex and heterogeneous system like climate networks than a fixed time delay most commonly used. On the other hand, the short comings of ES is its lack of vigorous test statistics for the significance level of the correlations, and the fact that only the events' time indices are synchronized while all information about how the relative intensities propagate within network framework is lost. The new method we present is motivated by the ES and borrows ideas from signal processing where a signal is represented by its intensity and frequency. Even though the anomaly signals are not periodic, the idea of phase synchronization is not far fetched. It brings into one umbrella, the traditionally known linear Intensity correlation methods like Pearson correlation, spear-man's rank or non-linear ones like mutual information with the ES for non-linear temporal synchronization. The intensity correlation is only performed where there is a temporal synchronization. The former just measures how constant the intensity differences are. In other words, how monotonic are the two functions. The overall measure of correlation and synchronization is the product of the two coefficients. Complex networks constructed by this technique has all the advantages inherent in each of the techniques it borrows. But, it is more superior and able to uncover many known and unknown dynamical features in rainfall field or any variable of interest. The main aim of this work is to develop a method that can identify the footprints of coherent or incoherent structures within the ICTZ, the African and the Indian monsoons and the ENSO signal on the tropical African continent and their temporal evolution.

Dynamic correlations at different time-scales with empirical mode decomposition

NASA Astrophysics Data System (ADS)

Nava, Noemi; Di Matteo, T.; Aste, Tomaso

2018-07-01

We introduce a simple approach which combines Empirical Mode Decomposition (EMD) and Pearson's cross-correlations over rolling windows to quantify dynamic dependency at different time scales. The EMD is a tool to separate time series into implicit components which oscillate at different time-scales. We apply this decomposition to intraday time series of the following three financial indices: the S&P 500 (USA), the IPC (Mexico) and the VIX (volatility index USA), obtaining time-varying multidimensional cross-correlations at different time-scales. The correlations computed over a rolling window are compared across the three indices, across the components at different time-scales and across different time lags. We uncover a rich heterogeneity of interactions, which depends on the time-scale and has important lead-lag relations that could have practical use for portfolio management, risk estimation and investment decisions.

Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

NASA Astrophysics Data System (ADS)

Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

2016-04-01

Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis.

Structural diversity of supercoiled DNA

PubMed Central

Irobalieva, Rossitza N.; Fogg, Jonathan M.; Catanese, Daniel J.; Sutthibutpong, Thana; Chen, Muyuan; Barker, Anna K.; Ludtke, Steven J.; Harris, Sarah A.; Schmid, Michael F.; Chiu, Wah; Zechiedrich, Lynn

2015-01-01

By regulating access to the genetic code, DNA supercoiling strongly affects DNA metabolism. Despite its importance, however, much about supercoiled DNA (positively supercoiled DNA, in particular) remains unknown. Here we use electron cryo-tomography together with biochemical analyses to investigate structures of individual purified DNA minicircle topoisomers with defined degrees of supercoiling. Our results reveal that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations. Moreover, we uncover striking differences in how the topoisomers handle torsional stress. As negative supercoiling increases, bases are increasingly exposed. Beyond a sharp supercoiling threshold, we also detect exposed bases in positively supercoiled DNA. Molecular dynamics simulations independently confirm the conformational heterogeneity and provide atomistic insight into the flexibility of supercoiled DNA. Our integrated approach reveals the three-dimensional structures of DNA that are essential for its function. PMID:26455586

Structural diversity of supercoiled DNA

NASA Astrophysics Data System (ADS)

Irobalieva, Rossitza N.; Fogg, Jonathan M.; Catanese, Daniel J.; Sutthibutpong, Thana; Chen, Muyuan; Barker, Anna K.; Ludtke, Steven J.; Harris, Sarah A.; Schmid, Michael F.; Chiu, Wah; Zechiedrich, Lynn

2015-10-01

By regulating access to the genetic code, DNA supercoiling strongly affects DNA metabolism. Despite its importance, however, much about supercoiled DNA (positively supercoiled DNA, in particular) remains unknown. Here we use electron cryo-tomography together with biochemical analyses to investigate structures of individual purified DNA minicircle topoisomers with defined degrees of supercoiling. Our results reveal that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations. Moreover, we uncover striking differences in how the topoisomers handle torsional stress. As negative supercoiling increases, bases are increasingly exposed. Beyond a sharp supercoiling threshold, we also detect exposed bases in positively supercoiled DNA. Molecular dynamics simulations independently confirm the conformational heterogeneity and provide atomistic insight into the flexibility of supercoiled DNA. Our integrated approach reveals the three-dimensional structures of DNA that are essential for its function.

Primary Characterization of Small RNAs in Symbiotic Nitrogen-Fixing Bacteria.

PubMed

Robledo, Marta; García-Tomsig, Natalia I; Jiménez-Zurdo, José I

2018-01-01

High-throughput transcriptome profiling (RNAseq) has uncovered large and heterogeneous populations of small noncoding RNA species (sRNAs) with potential regulatory roles in bacteria. A large fraction of sRNAs are differentially regulated and rely on protein-assisted antisense interactions to trans-encoded target mRNAs to fine-tune posttranscriptional reprogramming of gene expression in response to external cues. However, annotation and function of sRNAs are still largely overlooked in nonmodel bacteria with complex lifestyles. Here, we describe experimental protocols successfully applied for the accurate annotation, expression profiling and target mRNA identification of trans-acting sRNAs in the nitrogen-fixing α-rhizobium Sinorhizobium meliloti. The protocols presented here can be similarly applied for the characterization of trans-sRNAs in genetically tractable α-proteobacteria of agronomical or clinical relevance interacting with eukaryotic hosts.

Folk medicine used to heal malaria in Calabria (southern Italy)

PubMed Central

2010-01-01

In Italy, malaria was an endemic disease that was eradicated by the mid-20th century. This paper evaluates the prophylactic and therapeutic remedies used by folk medicine to cure malaria in Calabria (southern Italy). The data has been collected by analysing works of physicians, ethnographers, folklorists and specialists of the study of Calabrian history between the end of the 19th century and the 20th century. The data collected have allowed us to describe the most common cures used by the Calabrian people to treat malaria and the most evident symptoms of this disease, such as intermittent fever, hepato-spleenomegaly, asthenia and dropsy. This approach uncovered a heterogeneous corpus of empirical, magical and religious remedies, which the authors have investigated as evidences of past "expert medicine" and to verify their real effectiveness in the treatment of malaria. PMID:20849654

Effect of Ixekizumab Treatment on Work Productivity for Patients With Moderate-to-Severe Plaque Psoriasis: Analysis of Results From 3 Randomized Phase 3 Clinical Trials.

PubMed

Armstrong, April W; Lynde, Charles W; McBride, Sandy R; Ståhle, Mona; Edson-Heredia, Emily; Zhu, Baojin; Amato, David; Nikaï, Enkeleida; Yang, Fan Emily; Gordon, Kenneth B

2016-06-01

Therapies that reduce psoriasis symptoms may improve work productivity. To assess the effect of ixekizumab therapy on work productivity, measured by the Work Productivity and Activity Impairment-Psoriasis (WPAI-PSO). Three multicenter, randomized double-blind phase 3 trials conducted during the following periods: December 2011 through August 2014 (UNCOVER-1), May 2012 through April 2015 (UNCOVER-2), and August 2012 through July 2014 (UNCOVER-3). Adult outpatients with moderate-to-severe chronic plaque psoriasis were included. In UNCOVER-1, patients were randomized 1:1:1 to subcutaneous placebo or 80 mg ixekizumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 12 weeks; UNCOVER-2 and UNCOVER-3 also had an etanercept arm (50 mg twice weekly). Maintenance of initial ixekizumab response was evaluated in UNCOVER-1 and UNCOVER-2 during a randomized withdrawal period following week 12 through week 60. The WPAI-PSO questionnaire was administered at baseline and week 12 for all patients and at weeks 24, 36, 52, and 60 for patients in UNCOVER-1 and UNCOVER-2. Change in work productivity from baseline as measured by WPAI-PSO scores. Across trials, 5101 patients consented; 3866 were randomized (mean [SD] age, UNCOVER-1, 45.7 [12.9] y, 68.1% male; UNCOVER-2: 45.0 [13.0] y, 67.1% male; UNCOVER-3: 45.8 [13.1] y, 68.2% male). At week 12 in UNCOVER-1, the ixekizumab Q4W and ixekizumab Q2W groups showed significantly greater improvements in WPAI-PSO scores (least squares mean change from baseline [SE]) relative to placebo: absenteeism (-3.5 [0.87], P < .001; -2.6 [0.84], P = .003, respectively, vs 0.2 [0.88]), presenteeism (-18.8 [1.28], P < .001; -18.3 [1.24], P < .001, vs 0.5 [1.30]), work productivity loss (-20.6 [1.38], P < .001; -19.8 [1.33], P < .001, vs -0.8 [1.40]), and activity impairment (-24.5 [1.18], P < .001; -25.2 [1.15], P < .001, vs 0.8 [1.18]). Similar results were obtained for UNCOVER-2 and UNCOVER-3, with the exception of absenteeism with ixekizumab Q4W in UNCOVER-2. Additionally, ixekizumab-treated patients showed significantly greater improvements in WPAI-PSO scores vs etanercept-treated patients: UNCOVER-2: presenteeism, work productivity loss, activity impairment (P < .001 both doses), UNCOVER-3: activity impairment (ie, regular activities outside of work) (ixekizumab Q2W; P = .009). Improvements in WPAI-PSO scores at week 12 were sustained to at least week 60. Ixekizumab-treated patients reported short- and long-term improvements in work productivity, which could lead to reduced productivity-related cost burden in patients with psoriasis. clinicaltrials.gov Identifiers: NCT01474512, NCT01597245, NCT01646177.

Towards enhanced and interpretable clustering/classification in integrative genomics

PubMed Central

Lu, Yang Young; Lv, Jinchi; Fuhrman, Jed A.

2017-01-01

Abstract High-throughput technologies have led to large collections of different types of biological data that provide unprecedented opportunities to unravel molecular heterogeneity of biological processes. Nevertheless, how to jointly explore data from multiple sources into a holistic, biologically meaningful interpretation remains challenging. In this work, we propose a scalable and tuning-free preprocessing framework, Heterogeneity Rescaling Pursuit (Hetero-RP), which weighs important features more highly than less important ones in accord with implicitly existing auxiliary knowledge. Finally, we demonstrate effectiveness of Hetero-RP in diverse clustering and classification applications. More importantly, Hetero-RP offers an interpretation of feature importance, shedding light on the driving forces of the underlying biology. In metagenomic contig binning, Hetero-RP automatically weighs abundance and composition profiles according to the varying number of samples, resulting in markedly improved performance of contig binning. In RNA-binding protein (RBP) binding site prediction, Hetero-RP not only improves the prediction performance measured by the area under the receiver operating characteristic curves (AUC), but also uncovers the evidence supported by independent studies, including the distribution of the binding sites of IGF2BP and PUM2, the binding competition between hnRNPC and U2AF2, and the intron–exon boundary of U2AF2 [availability: https://github.com/younglululu/Hetero-RP]. PMID:28977511

Pleistocene glacial cycles drive isolation, gene flow and speciation in the high-elevation Andes.

PubMed

Nevado, Bruno; Contreras-Ortiz, Natalia; Hughes, Colin; Filatov, Dmitry A

2018-06-04

Mountain ranges are amongst the most species-rich habitats, with many large and rapid evolutionary radiations. The tempo and mode of diversification in these systems are key unanswered questions in evolutionary biology. Here we study the Andean Lupinus radiation to understand the processes driving very rapid diversification in montane systems. We use genomic and transcriptomic data of multiple species and populations, and apply phylogenomic and demographic analyses to test whether diversification proceeded without interspecific gene flow - as expected if Andean orogeny and geographic isolation were the main drivers of diversification - or if diversification was accompanied by gene flow, in which case other processes were probably involved. We uncover several episodes of gene flow between species, including very recent events likely to have been prompted by changes in habitat connectivity during Pleistocene glacial cycles. Furthermore, we find that gene flow between species was heterogeneously distributed across the genome. We argue that exceptionally fast diversification of Andean Lupinus was partly a result of Late Pleistocene glacial cycles, with associated cycles of expansion and contraction driving geographic isolation or secondary contact of species. Furthermore, heterogeneous gene flow across the genome suggests a role for selection and ecological speciation in rapid diversification in this system. © 2018 The Authors New Phytologist © 2018 New Phytologist Trust.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Somorjai

The International Symposium on Relations between Homogeneous and Heterogeneous Catalysis (ISHHC) has a long and distinguished history. Since 1974, in Brussels, this event has been held in Lyon, France (1977), Groeningen, The Netherlands (1981); Asilomar, California (1983); Novosibirsk, Russia (1986); Pisa, Italy (1989); Tokyo, Japan (1992); Balatonfuered, Hungary (1995); Southampton, United Kingdom (1999); Lyon, France (2001); Evanston, Illinois (2001) and Florence, Italy (2005). The aim of this international conference in Berkeley is to bring together practitioners in the three fields of catalysis, heterogeneous, homogeneous and enzyme, which utilize mostly nanosize particles. Recent advances in instrumentation, synthesis and reaction studies permitmore » the nanoscale characterization of the catalyst systems, often for the same reaction, under similar experimental conditions. It is hoped that this circumstance will permit the development of correlations of these three different fields of catalysis on the molecular level. To further this goal we aim to uncover and focus on common concepts that emerge from nanoscale studies of structures and dynamics of the three types of catalysts. Another area of focus that will be addressed is the impact on and correlation of nanosciences with catalysis. There is information on the electronic and atomic structures of nanoparticles and their dynamics that should have importance in catalyst design and catalytic activity and selectivity.« less

Population specific genetic heterogeneity of familial hypercholesterolemia in South Africa.

PubMed

Smyth, Natalie; Ramsay, Michèle; Raal, Frederick J

2018-04-01

To describe the prevalence and population-specific genetic heterogeneity of familial hypercholesterolemia in South Africa. This review highlights the paucity of data on familial hypercholesterolemia in South Africa, and the urgent need to uncover the mutation profiles in lipid-associated genes, causing an increase in LDL-cholesterol in the different ethnic groups. Case reports and small studies have shown that familial hypercholesterolemia, although apparently uncommon, is present in black Africans. Local founder effects have led to an increased prevalence of familial hypercholesterolemia in several South African populations: Afrikaner founder mutations (c.681 C>G, c.1285 G>A, c.523 G>A), Ashkenazi founder mutation (c.654_656del) and possible Indian founder mutation (c.2054 C>T). Preliminary data in black Africans with elevated LDL-cholesterol identified a possible common mutation, c.137_142del. The South African multiethnic society and well described founder effects emphasize the need for differential approaches to diagnosis and management of familial hypercholesterolemia. Studies involving larger cohorts and inclusive of different ethnicities are paramount to establishing an accurate prevalence of familial hypercholesterolemia in black Africans, not only in South Africa but in the Sub-Saharan African region. It is clear that the estimated world prevalence of one in 250 cannot be generally applied across African populations.

Extensive length variation in the ribosomal DNA intergenic spacer of yellow perch (Perca flavescens).

PubMed

Kakou, Bidénam; Angers, Bernard; Glémet, Hélène

2016-03-01

The intergenic spacer (IGS) is located between ribosomal RNA (rRNA) gene copies. Within the IGS, regulatory elements for rRNA gene transcription are found, as well as a varying number of other repetitive elements that are at the root of IGS length heterogeneity. This heterogeneity has been shown to have a functional significance through its effect on growth rate. Here, we present the structural organization of yellow perch (Perca flavescens) IGS based on its entire sequence, as well as the IGS length variation within a natural population. Yellow perch IGS structure has four discrete regions containing tandem repeat elements. For three of these regions, no specific length class was detected as allele size was seemingly normally distributed. However, for one repeat region, PCR amplification uncovered the presence of two distinctive IGS variants representing a length difference of 1116 bp. This repeat region was also devoid of any CpG sites despite a high GC content. Balanced selection may be holding the alleles in the population and would account for the high diversity of length variants observed for adjacent regions. Our study is an important precursor for further work aiming to assess the role of IGS length variation in influencing growth rate in fish.

Refining the Use of the Web (and Web Search) as a Language Teaching and Learning Resource

ERIC Educational Resources Information Center

Wu, Shaoqun; Franken, Margaret; Witten, Ian H.

2009-01-01

The web is a potentially useful corpus for language study because it provides examples of language that are contextualized and authentic, and is large and easily searchable. However, web contents are heterogeneous in the extreme, uncontrolled and hence "dirty," and exhibit features different from the written and spoken texts in other linguistic…

Lithium, Vanadium and Chromium Uptake Ability of Brassica juncea from Lithium Mine Tailings.

PubMed

Elektorowicz, M; Keropian, Z

2015-01-01

The potential for phytoremediation and phytostabilization of lithium in lieu with vanadium and chromium on a formulated acidic heterogeneous growth media engineered around lithium mine tailings, was investigated in four phases: (1) overall efficiency of the removal of the three metals, (2) bioaccumulation ratios of the three metals, (3) overall relative growth rate, and (4) translocation index of the three metals in the physiology of the hyperaccumulator plant. A pot study was conducted to assess the suitability of Brassica juncea (Indian mustard) in a phytoremediation process whereby it was lingered for eighty-six days under homogeneous growth conditions and irrigated bidaily with organic fertilizer amended with LiCl. A post harvest data analysis was achieved through ashing and the implementation of cold digestion procedure in a concentrated hydrochloric acidic matrix. In physiological efficiency parameters, the hyperaccumulator plant was twice as able to phytostabilize chromium and four times was able to phytostabilize vanadium in comparison to lithium. Moreover, it was extremely efficient in translocating and accumulating lithium inside its upper physiological sites, more so than chromium and vanadium, thereby demonstrating Indian mustard, as a hyperaccumulator plant, for phytoextraction and phytostabilization in an acidic heterogeneous rhizosphere, with an extremely low relative growth rate.

Extreme heterogeneity of polyadenylation sites in mRNAs encoding chloroplast RNA-binding proteins in Nicotiana plumbaginifolia.

PubMed

Klahre, U; Hemmings-Mieszczak, M; Filipowicz, W

1995-06-01

We have previously characterized nuclear cDNA clones encoding two RNA binding proteins, CP-RBP30 and CP-RBP-31, which are targeted to chloroplasts in Nicotiana plumbaginifolia. In this report we describe the analysis of the 3'-untranslated regions (3'-UTRs) in 22 CP-RBP30 and 8 CP-RBP31 clones which reveals that mRNAs encoding both proteins have a very complex polyadenylation pattern. Fourteen distinct poly(A) sites were identified among CP-RBP30 clones and four sites among the CP-RBP31 clones. The authenticity of the sites was confirmed by RNase A/T1 mapping of N. plumbaginifolia RNA. CP-RBP30 provides an extreme example of the heterogeneity known to be a feature of mRNA polyadenylation in higher plants. Using PCR we have demonstrated that CP-RBP genes in N. plumbaginifolia and N. sylvestris, in addition to the previously described introns interrupting the coding region, contain an intron located in the 3' non-coding part of the gene. In the case of the CP-RBP31, we have identified one polyadenylation event occurring in this intron.

Economic Evaluations of the Health Impacts of Weather-Related Extreme Events: A Scoping Review

PubMed Central

Schmitt, Laetitia H. M.; Graham, Hilary M.; White, Piran C. L.

2016-01-01

The frequency and severity of extreme events is expected to increase under climate change. There is a need to understand the economic consequences of human exposure to these extreme events, to underpin decisions on risk reduction. We undertook a scoping review of economic evaluations of the adverse health effects from exposure to weather-related extreme events. We searched PubMed, Embase and Web of Science databases with no restrictions to the type of evaluations. Twenty studies were included, most of which were recently published. Most studies have been undertaken in the U.S. (nine studies) or Asia (seven studies), whereas we found no studies in Africa, Central and Latin America nor the Middle East. Extreme temperatures accounted for more than a third of the pool of studies (seven studies), closely followed by flooding (six studies). No economic study was found on drought. Whilst studies were heterogeneous in terms of objectives and methodology, they clearly indicate that extreme events will become a pressing public health issue with strong welfare and distributional implications. The current body of evidence, however, provides little information to support decisions on the allocation of scarce resources between risk reduction options. In particular, the review highlights a significant lack of research attention to the potential cost-effectiveness of interventions that exploit the capacity of natural ecosystems to reduce our exposure to, or ameliorate the consequences of, extreme events. PMID:27834843

Mechanistic origin of dragon-kings in a population of competing agents

NASA Astrophysics Data System (ADS)

Johnson, N.; Tivnan, B.

2012-05-01

We analyze the mechanistic origins of the extreme behaviors that arise in an idealized model of a population of competing agents, such as traders in a market. These extreme behaviors exhibit the defining characteristics of `dragon-kings'. Our model comprises heterogeneous agents who repeatedly compete for some limited resource, making binary choices based on the strategies that they have in their possession. It generalizes the well-known Minority Game by allowing agents whose strategies have not made accurate recent predictions, to step out of the competition until their strategies improve. This generates a complex dynamical interplay between the number V of active agents (mimicking market volume) and the imbalance D between the decisions made (mimicking excess demand). The wide spectrum of extreme behaviors which emerge, helps to explain why no unique relationship has been identified between the price and volume during real market crashes and rallies.

Sustained response with ixekizumab treatment of moderate-to-severe psoriasis with scalp involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2, UNCOVER-3).

PubMed

Reich, Kristian; Leonardi, Craig; Lebwohl, Mark; Kerdel, Francisco; Okubo, Yukari; Romiti, Ricardo; Goldblum, Orin; Dennehy, Ellen B; Kerr, Lisa; Sofen, Howard

2017-06-01

Scalp is a frequently affected and difficult-to-treat area in psoriasis patients. We assessed the efficacy of ixekizumab in the treatment of patients with scalp psoriasis over 60 weeks using the Psoriasis Scalp Severity Index (PSSI). In three Phase 3, multicenter, double-blind, placebo-controlled trials, patients with moderate-to-severe psoriasis in UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224) and UNCOVER-3 (N = 1346) were randomized to subcutaneous 80 mg ixekizumab every two weeks (Q2W) or every four weeks (Q4W) after a 160 mg starting dose, or placebo through Week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg bi-weekly etanercept through Week 12. Patients entering the open-label long-term extension (LTE) (UNCOVER-3) received ixekizumab Q4W; UNCOVER-1 and UNCOVER-2 included a blinded maintenance period in which static physician global assessment (sPGA) 0/1 responders were re-randomized to placebo, ixekizumab Q4W, or 80 mg ixekizumab every 12 weeks (Q12W) through Week 60. In patients with moderate-to-severe psoriasis with baseline scalp involvement, PSSI 90 and 100 were achieved at Week 12 in higher percentages of patients treated with ixekizumab Q2W (81.7% and 74.6%) or ixekizumab Q4W (75.6% and 68.9%) compared with patients treated with placebo (7.6% and 6.7%; p < .001 each ixekizumab arm versus placebo) or etanercept (55.5% and 48.1%; p < .001 each ixekizumab arm versus etanercept). These outcomes were maintained through Week 60 of the maintenance (UNCOVER-1 and UNCOVER-2) and LTE (UNCOVER-3) period in patients who continued on ixekizumab Q4W. Ixekizumab was efficacious in treating scalp psoriasis in patients with moderate-to-severe psoriasis, with most patients achieving complete or near-complete resolution of scalp psoriasis and maintaining this response over 60 weeks.

Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain

PubMed Central

Pilaz, Louis-Jan; Silver, Debra L.

2015-01-01

The cerebral cortex, the brain structure responsible for our higher cognitive functions, is built during embryonic development in a process called corticogenesis. During corticogenesis, neural stem cells generate distinct populations of progenitors and excitatory neurons. These new neurons migrate radially in the cortex, eventually forming neuronal layers and establishing synaptic connections with other neurons both within and outside the cortex. Perturbations to corticogenesis can result in severe neurodevelopmental disorders, thus emphasizing the need to better understand molecular regulation of brain development. Recent studies in both model organisms and humans have collectively highlighted roles for post-transcriptional regulation in virtually all steps of corticogenesis. Genomic approaches have revealed global RNA changes associated with spatial and temporal regulation of cortical development. Additionally, genetic studies have uncovered RNA-binding proteins (RBPs) critical for cell proliferation, differentiation, and migration within the developing neocortex. Many of these same RBPs play causal roles in neurodevelopmental pathologies. In the developing neocortex, RBPs influence diverse steps of mRNA metabolism, including splicing, stability, translation, and localization. With the advent of new technologies, researchers have begun to uncover key transcripts regulated by these RBPs. Given the complexity of the developing mammalian cortex, a major challenge for the future will be to understand how dynamic RNA regulation occurs within heterogeneous cell populations, across space and time. In sum, post-transcriptional regulation has emerged as a critical mechanism for driving corticogenesis and exciting direction of future research. PMID:26088328

TREM2 is associated with increased risk for Alzheimer's disease in African Americans.

PubMed

Jin, Sheng Chih; Carrasquillo, Minerva M; Benitez, Bruno A; Skorupa, Tara; Carrell, David; Patel, Dwani; Lincoln, Sarah; Krishnan, Siddharth; Kachadoorian, Michaela; Reitz, Christiane; Mayeux, Richard; Wingo, Thomas S; Lah, James J; Levey, Allan I; Murrell, Jill; Hendrie, Hugh; Foroud, Tatiana; Graff-Radford, Neill R; Goate, Alison M; Cruchaga, Carlos; Ertekin-Taner, Nilüfer

2015-04-10

TREM2 encodes for triggering receptor expressed on myeloid cells 2 and has rare, coding variants that associate with risk for late-onset Alzheimer's disease (LOAD) in Caucasians of European and North-American origin. This study evaluated the role of TREM2 in LOAD risk in African-American (AA) subjects. We performed exonic sequencing and validation in two independent cohorts of >800 subjects. We selected six coding variants (p.R47H, p.R62H, p.D87N, p.E151K, p.W191X, and p.L211P) for case-control analyses in a total of 906 LOAD cases vs. 2,487 controls. We identified significant LOAD risk association with p.L211P (p=0.01, OR=1.27, 95%CI=1.05-1.54) and suggestive association with p.W191X (p=0.08, OR=1.35, 95%CI=0.97-1.87). Conditional analysis suggests that p.L211P, which is in linkage disequilibrium with p.W191X, may be the stronger variant of the two, but does not rule out independent contribution of the latter. TREM2 p.L211P resides within the cytoplasmic domain and p.W191X is a stop-gain mutation within the shorter TREM-2V transcript. The coding variants within the extracellular domain of TREM2 previously shown to confer LOAD risk in Caucasians were extremely rare in our AA cohort and did not associate with LOAD risk. Our findings suggest that TREM2 coding variants also confer LOAD risk in AA, but implicate variants within different regions of the gene than those identified for Caucasian subjects. These results underscore the importance of investigating different ethnic populations for disease risk variant discovery, which may uncover allelic heterogeneity with potentially diverse mechanisms of action.

Partially Covered Metal Stents May Not Prolong Stent Patency Compared to Uncovered Stents in Unresectable Malignant Distal Biliary Obstruction.

PubMed

Kim, Jae Yun; Ko, Gyu Bong; Lee, Tae Hoon; Park, Sang-Heum; Lee, Yun Nah; Cho, Young Sin; Jung, Yunho; Chung, Il-Kwun; Choi, Hyun Jong; Cha, Sang-Woo; Moon, Jong Ho; Cho, Young Deok; Kim, Sun-Joo

2017-05-15

Controversy still exists regarding the benefits of covered self-expandable metal stents (SEMSs) compared to uncovered SEMSs. We aimed to compare the patency and stent-related adverse events of partially covered SEMSs (PC-SEMSs) and uncovered SEMSs in unresectable malignant distal biliary obstruction. A total of 134 patients who received a PC-SEMS or uncovered SEMS for palliation of unresectable malignant distal biliary obstruction were reviewed retrospectively. The main outcome measures were stent patency, stent-related adverse events, and overall survival. The median stent patency was 118 days (range, 3 to 802 days) with PC-SEMSs and 105 days (range, 2 to 485 days) with uncovered SEMSs (p=0.718). The overall endoscopic revision rate due to stent dysfunction was 36.6% (26/71) with PC-SEMSs and 36.5% (23/63) with uncovered SEMSs (p=0.589). Tumor ingrowth was more frequent with uncovered SEMSs (4.2% vs 19.1%, p=0.013), but migration was more frequent with PC-SEMSs (11.2% vs 1.5%, p=0.04). The incidence of stent-related adverse events was 2.8% (2/71) with PC-SEMSs and 9.5% (6/63) with uncovered SEMSs (p=0.224). The median overall survival was 166 days with PC-SEMSs and 168 days with uncovered SEMSs (p=0.189). Compared to uncovered SEMSs, PC-SEMSs did not prolong stent patency in unresectable malignant distal biliary obstruction. Stent migration was more frequent with PC-SEMSs. However, tumor ingrowth was less frequent with PC-SEMSs compared to uncovered SEMSs.

Partially Covered Metal Stents May Not Prolong Stent Patency Compared to Uncovered Stents in Unresectable Malignant Distal Biliary Obstruction

PubMed Central

Kim, Jae Yun; Ko, Gyu Bong; Lee, Tae Hoon; Park, Sang-Heum; Lee, Yun Nah; Cho, Young Sin; Jung, Yunho; Chung, Il-Kwun; Choi, Hyun Jong; Cha, Sang-Woo; Moon, Jong Ho; Cho, Young Deok; Kim, Sun-Joo

2017-01-01

Background/Aims Controversy still exists regarding the benefits of covered self-expandable metal stents (SEMSs) compared to uncovered SEMSs. We aimed to compare the patency and stent-related adverse events of partially covered SEMSs (PC-SEMSs) and uncovered SEMSs in unresectable malignant distal biliary obstruction. Methods A total of 134 patients who received a PC-SEMS or uncovered SEMS for palliation of unresectable malignant distal biliary obstruction were reviewed retrospectively. The main outcome measures were stent patency, stent-related adverse events, and overall survival. Results The median stent patency was 118 days (range, 3 to 802 days) with PC-SEMSs and 105 days (range, 2 to 485 days) with uncovered SEMSs (p=0.718). The overall endoscopic revision rate due to stent dysfunction was 36.6% (26/71) with PC-SEMSs and 36.5% (23/63) with uncovered SEMSs (p=0.589). Tumor ingrowth was more frequent with uncovered SEMSs (4.2% vs 19.1%, p=0.013), but migration was more frequent with PC-SEMSs (11.2% vs 1.5%, p=0.04). The incidence of stent-related adverse events was 2.8% (2/71) with PC-SEMSs and 9.5% (6/63) with uncovered SEMSs (p=0.224). The median overall survival was 166 days with PC-SEMSs and 168 days with uncovered SEMSs (p=0.189). Conclusions Compared to uncovered SEMSs, PC-SEMSs did not prolong stent patency in unresectable malignant distal biliary obstruction. Stent migration was more frequent with PC-SEMSs. However, tumor ingrowth was less frequent with PC-SEMSs compared to uncovered SEMSs. PMID:28208003

77 FR 12227 - Long Term 2 Enhanced Surface Water Treatment Rule: Uncovered Finished Water Reservoirs; Public...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-29

... Water Treatment Rule: Uncovered Finished Water Reservoirs; Public Meeting AGENCY: Environmental... review of the uncovered finished water reservoir requirement in the Long Term 2 Enhanced Surface Water... uncovered finished water reservoir requirement and the agency's Six Year Review process. EPA also plans to...

Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis.

PubMed

Farschtschi, Said; Mautner, Victor-Felix; Pham, Mirko; Nguyen, Rosa; Kehrer-Sawatzki, Hildegard; Hutter, Sonja; Friedrich, Reinhard E; Schulz, Alexander; Morrison, Helen; Jones, David T W; Bendszus, Martin; Bäumer, Philipp

2016-10-01

Schwannomatosis is a genetic disorder characterized by the occurrence of multiple peripheral schwannomas. Segmental schwannomatosis is diagnosed when schwannomas are restricted to 1 extremity and is thought to be caused by genetic mosaicism. We studied 5 patients with segmental schwannomatosis through microstructural magnetic resonance neurography and mutation analysis of NF2, SMARCB1, and LZTR1. In 4 of 5 patients, subtle fascicular nerve lesions were detected in clinically unaffected extremities. Two patients exhibited LZTR1 germline mutations. This appears contrary to a simple concept of genetic mosaicism and suggests more complex and heterogeneous mechanisms underlying the phenotype of segmental schwannomatosis than previously thought. Ann Neurol 2016;80:625-628. © 2016 American Neurological Association.

Evidence for minimal oxygen heterogeneity in the healthy human pulmonary acinus

PubMed Central

Tawhai, Merryn H.

2011-01-01

It has been suggested that the human pulmonary acinus operates at submaximal efficiency at rest due to substantial spatial heterogeneity in the oxygen partial pressure (Po2) in alveolar air within the acinus. Indirect measurements of alveolar air Po2 could theoretically mask significant heterogeneity if intra-acinar perfusion is well matched to Po2. To investigate the extent of intra-acinar heterogeneity, we developed a computational model with anatomically based structure and biophysically based equations for gas exchange. This model yields a quantitative prediction of the intra-acinar O2 distribution that cannot be measured directly. Temporal and spatial variations in Po2 in the intra-acinar air and blood are predicted with the model. The model, representative of a single average acinus, has an asymmetric multibranching respiratory airways geometry coupled to a symmetric branching conducting airways geometry. Advective and diffusive O2 transport through the airways and gas exchange into the capillary blood are incorporated. The gas exchange component of the model includes diffusion across the alveolar air-blood membrane and O2-hemoglobin binding. Contrary to previous modeling studies, simulations show that the acinus functions extremely effectively at rest, with only a small degree of intra-acinar Po2 heterogeneity. All regions of the model acinus, including the peripheral generations, maintain a Po2 >100 mmHg. Heterogeneity increases slightly when the acinus is stressed by exercise. However, even during exercise the acinus retains a reasonably homogeneous gas phase. PMID:21071589

Non-equilibrium thermodynamics theory of econometric source discovery for large data analysis

NASA Astrophysics Data System (ADS)

van Bergem, Rutger; Jenkins, Jeffrey; Benachenhou, Dalila; Szu, Harold

2014-05-01

Almost all consumer and firm transactions are achieved using computers and as a result gives rise to increasingly large amounts of data available for analysts. The gold standard in Economic data manipulation techniques matured during a period of limited data access, and the new Large Data Analysis (LDA) paradigm we all face may quickly obfuscate most tools used by Economists. When coupled with an increased availability of numerous unstructured, multi-modal data sets, the impending 'data tsunami' could have serious detrimental effects for Economic forecasting, analysis, and research in general. Given this reality we propose a decision-aid framework for Augmented-LDA (A-LDA) - a synergistic approach to LDA which combines traditional supervised, rule-based Machine Learning (ML) strategies to iteratively uncover hidden sources in large data, the artificial neural network (ANN) Unsupervised Learning (USL) at the minimum Helmholtz free energy for isothermal dynamic equilibrium strategies, and the Economic intuitions required to handle problems encountered when interpreting large amounts of Financial or Economic data. To make the ANN USL framework applicable to economics we define the temperature, entropy, and energy concepts in Economics from non-equilibrium molecular thermodynamics of Boltzmann viewpoint, as well as defining an information geometry, on which the ANN can operate using USL to reduce information saturation. An exemplar of such a system representation is given for firm industry equilibrium. We demonstrate the traditional ML methodology in the economics context and leverage firm financial data to explore a frontier concept known as behavioral heterogeneity. Behavioral heterogeneity on the firm level can be imagined as a firm's interactions with different types of Economic entities over time. These interactions could impose varying degrees of institutional constraints on a firm's business behavior. We specifically look at behavioral heterogeneity for firms that are operating with the label of `Going-Concern' and firms labeled according to institutional influence they may be experiencing, such as constraints on firm hiring/spending while in a Bankruptcy or a Merger procedure. Uncovering invariant features, or behavioral data metrics from observable firm data in an economy can greatly benefit the FED, World Bank, etc. We find that the ML/LDA communities can benefit from Economic intuitions just as much as Economists can benefit from generic data exploration tools. The future of successful Economic data understanding, modeling, simulation, and visualization can be amplified by new A-LDA models and approaches for new and analogous models of Economic system dynamics. The potential benefits of improved economic data analysis and real time decision aid tools are numerous for researchers, analysts, and federal agencies who all deal with increasingly large amounts of complex data to support their decision making.

SharP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venkata, Manjunath Gorentla; Aderholdt, William F

The pre-exascale systems are expected to have a significant amount of hierarchical and heterogeneous on-node memory, and this trend of system architecture in extreme-scale systems is expected to continue into the exascale era. along with hierarchical-heterogeneous memory, the system typically has a high-performing network ad a compute accelerator. This system architecture is not only effective for running traditional High Performance Computing (HPC) applications (Big-Compute), but also for running data-intensive HPC applications and Big-Data applications. As a consequence, there is a growing desire to have a single system serve the needs of both Big-Compute and Big-Data applications. Though the system architecturemore » supports the convergence of the Big-Compute and Big-Data, the programming models and software layer have yet to evolve to support either hierarchical-heterogeneous memory systems or the convergence. A programming abstraction to address this problem. The programming abstraction is implemented as a software library and runs on pre-exascale and exascale systems supporting current and emerging system architecture. Using distributed data-structures as a central concept, it provides (1) a simple, usable, and portable abstraction for hierarchical-heterogeneous memory and (2) a unified programming abstraction for Big-Compute and Big-Data applications.« less

Homogeneous Combinations of ASD-ADHD Traits and Their Cognitive and Behavioral Correlates in a Population-Based Sample.

PubMed

van der Meer, Jolanda M J; Lappenschaar, Martijn G A; Hartman, Catharina A; Greven, Corina U; Buitelaar, Jan K; Rommelse, Nanda N J

2017-07-01

Autism Spectrum Disorders (ASD) and ADHD are assumed to be the extreme manifestations of continuous heterogeneous traits that frequently co-occur. This study aims to identify subgroups of children with distinct ASD-ADHD trait profiles in the general population, using measures sensitive across both trait continua, and show how these subgroups differ in cognitive functioning. We examined 378 children (6-13 years) from a population-based sample. Latent class analyses (LCA) detected three concordant classes with low (10.1%), medium (54.2%), or high (13.2%) scores on both traits, and two discordant classes with more ADHD than ASD characteristics (ADHD > ASD, 18.3%) and vice versa (ASD > ADHD, 4.2%). Findings suggest that ASD and ADHD traits usually are strongly related in the unaffected population, and that a minority of children displays atypical discordant trait profiles characterized by differential visual-spatial functioning. This dissociation suggests that heterogeneity in ASD and ADHD is rooted in heterogeneity in the lower unaffected end of the distribution.

Algorithms for differentiating between images of heterogeneous tissue across fluorescence microscopes.

PubMed

Chitalia, Rhea; Mueller, Jenna; Fu, Henry L; Whitley, Melodi Javid; Kirsch, David G; Brown, J Quincy; Willett, Rebecca; Ramanujam, Nimmi

2016-09-01

Fluorescence microscopy can be used to acquire real-time images of tissue morphology and with appropriate algorithms can rapidly quantify features associated with disease. The objective of this study was to assess the ability of various segmentation algorithms to isolate fluorescent positive features (FPFs) in heterogeneous images and identify an approach that can be used across multiple fluorescence microscopes with minimal tuning between systems. Specifically, we show a variety of image segmentation algorithms applied to images of stained tumor and muscle tissue acquired with 3 different fluorescence microscopes. Results indicate that a technique called maximally stable extremal regions followed by thresholding (MSER + Binary) yielded the greatest contrast in FPF density between tumor and muscle images across multiple microscopy systems.

Covered versus uncovered self-expandable metal stents for malignant biliary strictures: A meta-analysis and systematic review.

PubMed

Moole, Harsha; Bechtold, Matthew L; Cashman, Micheal; Volmar, Fritz H; Dhillon, Sonu; Forcione, David; Taneja, Deepak; Puli, Srinivas R

2016-09-01

Self-expandable metal stents (SEMS) are used for palliating inoperable malignant biliary strictures. It is unclear if covered metal stents are superior to uncovered metal stents in these patients. We compared clinical outcomes in patients with covered and uncovered stents. Studies using covered and uncovered metallic stents for palliation in patients with malignant biliary stricture were reviewed. Articles were searched in MEDLINE, PubMed, and Ovid journals. Fixed and random effects models were used to calculate the pooled proportions. Initial search identified 1436 reference articles, of which 132 were selected and reviewed. Thirteen studies (n = 2239) for covered and uncovered metallic stents which met the inclusion criteria were included in this analysis. Odds ratio for stent occlusion rates in covered vs. uncovered stents was 0.79 (95 % CI = 0.65 to 0.96). Survival benefit in patients with covered vs. uncovered stents showed the odds ratio to be 1.29 (95 % CI = 0.95 to 1.74). Pooled odds ratio for migration of covered vs. uncovered stents was 9.9 (95 % CI = 4.5 to 22.3). Covered stents seemed to have significantly lesser occlusion rates, increased odds of migration, and increased odds of pancreatitis compared to uncovered stents. There was no statistically significant difference in the survival benefit, overall adverse event rate, and patency period of covered vs. uncovered metal stents in patients with malignant biliary strictures.

Meta-analysis of two studies in the presence of heterogeneity with applications in rare diseases.

PubMed

Friede, Tim; Röver, Christian; Wandel, Simon; Neuenschwander, Beat

2017-07-01

Random-effects meta-analyses are used to combine evidence of treatment effects from multiple studies. Since treatment effects may vary across trials due to differences in study characteristics, heterogeneity in treatment effects between studies must be accounted for to achieve valid inference. The standard model for random-effects meta-analysis assumes approximately normal effect estimates and a normal random-effects model. However, standard methods based on this model ignore the uncertainty in estimating the between-trial heterogeneity. In the special setting of only two studies and in the presence of heterogeneity, we investigate here alternatives such as the Hartung-Knapp-Sidik-Jonkman method (HKSJ), the modified Knapp-Hartung method (mKH, a variation of the HKSJ method) and Bayesian random-effects meta-analyses with priors covering plausible heterogeneity values; R code to reproduce the examples is presented in an appendix. The properties of these methods are assessed by applying them to five examples from various rare diseases and by a simulation study. Whereas the standard method based on normal quantiles has poor coverage, the HKSJ and mKH generally lead to very long, and therefore inconclusive, confidence intervals. The Bayesian intervals on the whole show satisfying properties and offer a reasonable compromise between these two extremes. © 2016 The Authors. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dupuytren disease: on our way to a cure?

PubMed

Degreef, Ilse; De Smet, Luc

2013-06-01

Despite its high prevalence, the clinical presentation and severity of Dupuytren disease is extremely variable. The disease features a broad spectrum of symptoms, from simple nodules without the slightest clinical impact towards an extremely disabling form requiring multiple surgical procedures, sometimes even partial hand amputations. Recurrence after surgery is considered a failure for both patient and surgeon, but its definition is vague. The term 'recontracture' was coined by a patient and reflects the disappointment of recurrent disease. Wether or not a treatment option will insure a definite result, may depend more on the severity of the disease, which is patient specific, than on the treatment method itself. If a patient presents with Dupuytren disease, one should not merely evaluate his hands. Different clinical and personal history features may uncover a severe fibrosis diathesis and both correct information to the patient and an individualized treatment plan are needed. In the near future, a simple genetic test may help to identify patients at risk. Similar to the evolving knowledge and treatment modalities seen in rheumatoid arthritis, treatment of Dupuytren disease is likely to advance in the direction of disease control with pharmacotherapy and single shot minimal invasive enzymatic fasciotomy with collagenase to correct established contractures.

Black-hole Merger Simulations for LISA Science

NASA Technical Reports Server (NTRS)

Kelly, Bernard J.; Baker, John G.; vanMeter, James R.; Boggs, William D.; Centrella, Joan M.; McWilliams, Sean T.

2009-01-01

The strongest expected sources of gravitational waves in the LISA band are the mergers of massive black holes. LISA may observe these systems to high redshift, z>10, to uncover details of the origin of massive black holes, and of the relationship between black holes and their host structures, and structure formation itself. These signals arise from the final stage in the development of a massive black-hole binary emitting strong gravitational radiation that accelerates the system's inspiral toward merger. The strongest part of the signal, at the point of merger, carries much information about the system and provides a probe of extreme gravitational physics. Theoretical predictions for these merger signals rely on supercomputer simulations to solve Einstein's equations. We discuss recent numerical results and their impact on LISA science expectations.

Distributed sensor coordination for advanced energy systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tumer, Kagan

Motivation: The ability to collect key system level information is critical to the safe, efficient and reliable operation of advanced power systems. Recent advances in sensor technology have enabled some level of decision making directly at the sensor level. However, coordinating large numbers of sensors, particularly heterogeneous sensors, to achieve system level objectives such as predicting plant efficiency, reducing downtime or predicting outages requires sophisticated coordination algorithms. Indeed, a critical issue in such systems is how to ensure the interaction of a large number of heterogenous system components do not interfere with one another and lead to undesirable behavior. Objectivesmore » and Contributions: The long-term objective of this work is to provide sensor deployment, coordination and networking algorithms for large numbers of sensors to ensure the safe, reliable, and robust operation of advanced energy systems. Our two specific objectives are to: 1. Derive sensor performance metrics for heterogeneous sensor networks. 2. Demonstrate effectiveness, scalability and reconfigurability of heterogeneous sensor network in advanced power systems. The key technical contribution of this work is to push the coordination step to the design of the objective functions of the sensors, allowing networks of heterogeneous sensors to be controlled. By ensuring that the control and coordination is not specific to particular sensor hardware, this approach enables the design and operation of large heterogeneous sensor networks. In addition to the coordination coordination mechanism, this approach allows the system to be reconfigured in response to changing needs (e.g., sudden external events requiring new responses) or changing sensor network characteristics (e.g., sudden changes to plant condition). Impact: The impact of this work extends to a large class of problems relevant to the National Energy Technology Laboratory including sensor placement, heterogeneous sensor coordination, and sensor network control in advanced power systems. Each application has specific needs, but they all share the one crucial underlying problem: how to ensure that the interactions of a large number of heterogenous agents lead to coordinated system behavior. This proposal describes a new paradigm that addresses that very issue in a systematic way. Key Results and Findings: All milestones have been completed. Our results demonstrate that by properly shaping agent objective functions, we can develop large (up to 10,000 devices) heterogeneous sensor networks with key desirable properties. The first milestone shows that properly choosing agent-specific objective functions increases system performance by up to 99.9% compared to global evaluations. The second milestone shows evolutionary algorithms learn excellent sensor network coordination policies prior to network deployment, and these policies can be refined online once the network is deployed. The third milestone shows the resulting sensor networks networks are extremely robust to sensor noise, where networks with up to 25% sensor noise are capable of providing measurements with errors on the order of 10⁻³. The fourth milestone shows the resulting sensor networks are extremely robust to sensor failure, with 25% of the sensors in the system failing resulting in no significant performance losses after system reconfiguration.« less

Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution.

PubMed

Braxton, David R; Zhang, Ray; Morrissette, Jennifer D; Loaiza-Bonilla, Arturo; Furth, Emma E

2016-10-01

Cancer somatic genetic evolution is a direct contributor to heterogeneity at the clonal and molecular level in colorectal adenocarcinoma (COAD). We sought to determine the extent to which genetic evolution may be detected in COAD in routinely obtained single clinical specimens and establish clinical significance with regard to clinicopathologic and outcome data. One hundred and twenty three cases of routinely collected mismatch repair proficient COAD were sequenced on the Illumina Truseq Amplicon assay. Measures of intratumoral heterogeneity and the preferential timing of mutational events were assessed and compared to clinicopathologic data. Survival subanalysis was performed on 55 patients. Patient age (p = 0.013) and specimen percent tumor (p = 0.033) was associated with clonal diversity, and biopsy (p = 0.044) and metastasis (p = 0.044) returned fewer mutations per case. APC and TP53 mutations preferentially occurred early while alterations in FBXW7, FLT3, SMAD4, GNAS and PTEN preferentially occurred as late events. Temporal heterogeneity was evident in KRAS and PIK3CA mutations. Hierarchical clustering revealed a TP53 mutant subtype and a MAPK-PIK3CA subtype with differing patterns of late mutational events. Survival subanalysis showed a decreased median progression free survival for the MAPK-PIK3CA subtype (8 months vs. 13 months; univariate logrank p = 0.0380, cox model p= 0.018). Neoadjuvant therapy associated mutations were found for ERBB2 (p = 0.0481) and FBXW7 (p = 0.015). Our data indicate novel molecular subtypes of mismatch repair proficient COAD display differing patterns of genetic evolution which correlate with clinical outcomes. Furthermore, we report treatment acquired and/or selected mutations in ERBB2 and FBXW7. © 2016 UICC.

p57KIP2 expression and loss of heterozygosity during immortal conversion of cultured human mammary epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nijjar, Tarlochan; Wigington, Don; Garbe, James C.

1999-08-01

The authors have uncovered a novel role for the cyclin-dependent kinase inhibitor, p57KIP2, during the immortalization of cultured human mammary epithelial cells (HMEC). HMEC immortalized following chemical carcinogen exposure initially expressed little or no telomerase activity, and their telomeres continued to shorten with passage. Cell populations whose mean terminal restriction fragment (TRF) length declined and exhibited slow heterogeneous growth, and contained many non-proliferative cells. These conditionally immortal HMEC cultures accumulated large quantities of p57 protein. With continued passage, the conditionally immortal cell populations very graduall2048nverted to a fully immortal phenotype of good uniform growth, expression of high levels of telomerasemore » activity, and stabilization of telomere length. The fully immortal good growing HMEC did not accumulate p57 in G0 or during the cell cycle. DNA and RNA analysis of mass populations and individual subclones of conditionally immortal HMEC line 184A1 showed that continued growth of conditionally immortal cells with critically short telomeres was repeatedly accompanied by loss of the expressed p57 allele, and transient expression of the previously imprinted allele. Conditionally immortal 184A1 with mean TRF > 3 kb infected with retroviruses containing the p57 gene exhibited premature slow heterogeneous growth. Conversely, exogenous expression of hTERT, the catalytic subunit of telomerase, in 184A1 with mean TRF > 3 kb prevented both the slow heterogeneous growth phase and accumulation of p57 in cycling populations. These data indicate that in HMEC which have overcome replicative senescence, p57 may provide an additional barrier against indefinite proliferation. Overcoming p57 mediated growth inhibition in these cells may be crucial for acquisition of the unlimited growth potential thought to be critical for malignant progression.« less

Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach

PubMed Central

Scott, Milcah C.; Sarver, Aaron L.; Gavin, Katherine J.; Thayanithy, Venugopal; Getzy, David M.; Newman, Robert A.; Cutter, Gary R.; Lindblad-Toh, Kerstin; Kisseberth, William C.; Hunter, Lawrence E.; Subramanian, Subbaya; Breen, Matthew; Modiano, Jaime F.

2011-01-01

The heterogeneous and chaotic nature of osteosarcoma has confounded accurate molecular classification, prognosis, and prediction for this tumor. The occurrence of spontaneous osteosarcoma is largely confined to humans and dogs. While the clinical features are remarkably similar in both species, the organization of dogs into defined breeds provides a more homogeneous genetic background that may increase the likelihood to uncover molecular subtypes for this complex disease. We thus hypothesized that molecular profiles derived from canine osteosarcoma would aid in molecular subclassification of this disease when applied to humans. To test the hypothesis, we performed genome wide gene expression profiling in a cohort of dogs with osteosarcoma, primarily from high-risk breeds. To further reduce inter-sample heterogeneity, we assessed tumor-intrinsic properties through use of an extensive panel of osteosarcoma-derived cell lines. We observed strong differential gene expression that segregated samples into two groups with differential survival probabilities. Groupings were characterized by the inversely correlated expression of genes associated with G2/M transition and DNA damage checkpoint and microenvironment-interaction categories. This signature was preserved in data from whole tumor samples of three independent dog osteosarcoma cohorts, with stratification into the two expected groups. Significantly, this restricted signature partially overlapped a previously defined, predictive signature for soft tissue sarcomas, and it unmasked orthologous molecular subtypes and their corresponding natural histories in five independent data sets from human patients with osteosarcoma. Our results indicate that the narrower genetic diversity of dogs can be utilized to group complex human osteosarcoma into biologically and clinically relevant molecular subtypes. This in turn may enhance prognosis and prediction, and identify relevant therapeutic targets. PMID:21621658

Role of Network Science in the Study of Anesthetic State Transitions.

PubMed

Lee, UnCheol; Mashour, George A

2018-04-23

The heterogeneity of molecular mechanisms, target neural circuits, and neurophysiologic effects of general anesthetics makes it difficult to develop a reliable and drug-invariant index of general anesthesia. No single brain region or mechanism has been identified as the neural correlate of consciousness, suggesting that consciousness might emerge through complex interactions of spatially and temporally distributed brain functions. The goal of this review article is to introduce the basic concepts of networks and explain why the application of network science to general anesthesia could be a pathway to discover a fundamental mechanism of anesthetic-induced unconsciousness. This article reviews data suggesting that reduced network efficiency, constrained network repertoires, and changes in cortical dynamics create inhospitable conditions for information processing and transfer, which lead to unconsciousness. This review proposes that network science is not just a useful tool but a necessary theoretical framework and method to uncover common principles of anesthetic-induced unconsciousness.

Liver-resident NK cells and their potential functions.

PubMed

Peng, Hui; Sun, Rui

2017-09-18

Natural killer (NK) cells represent a heterogeneous population of innate lymphocytes with phenotypically and functionally distinct subsets. In particular, recent studies have identified a unique subset of NK cells residing within the liver that are maintained as tissue-resident cells, confer antigen-specific memory responses and exhibit different phenotypical and developmental characteristics compared with conventional NK (cNK) cells. These findings have encouraged researchers to uncover tissue-resident NK cells at other sites, and detailed analyses have revealed that these tissue-resident NK cells share many similarities with liver-resident NK cells and tissue-resident memory T cells. Here, we present a brief historical perspective on the discovery of liver-resident NK cells and discuss their relationship to cNK cells and other emerging NK cell subsets and their potential functions.Cellular &Molecular Immunology advance online publication, 18 September 2017; doi:10.1038/cmi.2017.72.

Multiple geophysical surveys for old landfill monitoring in Singapore.

PubMed

Yin, Ke; Tong, Huanhuan; Giannis, Apostolos; Wang, Jing-Yuan; Chang, Victor W-C

2017-01-01

One-dimensional boring presents limitations on mapping the refuse profile in old landfills owning to waste heterogeneity. Electrical imaging (EI) and multiple-analysis of surface wave (MASW) were hereby deployed at an old dumping ground in Singapore to explore the subsurface in relation to geotechnical analysis. MASW estimated the refuse boundary with a higher precision as compared to EI, due to its endurance for moisture variation. EI and MASW transection profiles suggested spots of interest, e.g., refuse pockets and leachate mounds. 3D inversion of EI and MASW data further illustrated the transformation dynamics derived by natural attenuation, for instance the preferential infiltration pathway. Comparison of geophysical surveys at different years uncovered the subterranean landfill conditions, indicating strong impacts induced by aging, precipitation, and settlement. This study may shed light on a characterization framework of old landfills via combined geophysical models, thriving landfill knowledge with a higher creditability.

Causal Structure of Brain Physiology after Brain Injury from Subarachnoid Hemorrhage.

PubMed

Claassen, Jan; Rahman, Shah Atiqur; Huang, Yuxiao; Frey, Hans-Peter; Schmidt, J Michael; Albers, David; Falo, Cristina Maria; Park, Soojin; Agarwal, Sachin; Connolly, E Sander; Kleinberg, Samantha

2016-01-01

High frequency physiologic data are routinely generated for intensive care patients. While massive amounts of data make it difficult for clinicians to extract meaningful signals, these data could provide insight into the state of critically ill patients and guide interventions. We develop uniquely customized computational methods to uncover the causal structure within systemic and brain physiologic measures recorded in a neurological intensive care unit after subarachnoid hemorrhage. While the data have many missing values, poor signal-to-noise ratio, and are composed from a heterogeneous patient population, our advanced imputation and causal inference techniques enable physiologic models to be learned for individuals. Our analyses confirm that complex physiologic relationships including demand and supply of oxygen underlie brain oxygen measurements and that mechanisms for brain swelling early after injury may differ from those that develop in a delayed fashion. These inference methods will enable wider use of ICU data to understand patient physiology.

Potential genetic polymorphisms predicting polycystic ovary syndrome.

PubMed

Chen, Yao; Fang, Shu-Ying

2018-05-01

Polycystic ovary syndrome (PCOS) is a heterogenous endocrine disorder with typical symptoms of oligomenorrhoea, hyperandrogenism, hirsutism, obesity, insulin resistance and increased risk of type 2 diabetes mellitus. Extensive evidence indicates that PCOS is a genetic disease and numerous biochemical pathways have been linked with its pathogenesis. A number of genes from these pathways have been investigated, which include those involved with steroid hormone biosynthesis and metabolism, action of gonadotropin and gonadal hormones, folliculogenesis, obesity and energy regulation, insulin secretion and action and many others. In this review, we summarize the historical and recent findings in genetic polymorphisms of PCOS from the relevant publications and outline some genetic polymorphisms that are potentially associated with the risk of PCOS. This information could uncover candidate genes associating with PCOS, which will be valuable for the development of novel diagnostic and treatment platforms for PCOS patients. © 2018 The authors.

Psychological Distress among Victimized Women on Probation and Parole: A Latent Class Analysis

PubMed Central

Golder, Seana; Engstrom, Malitta; Hall, Martin T.; Higgins, George; Logan, TK

2015-01-01

Latent class analysis was used to identify subgroups of victimized women (N=406) on probation and parole differentiated by levels of general psychological distress. The nine primary symptom dimensions from the Brief Symptom Inventory (BSI) were used individually as latent class indicators (Derogatis, 1993). Results identified three classes of women characterized by increasing levels of psychological distress; classes were further differentiated by posttraumatic stress disorder symptoms, cumulative victimization, substance use and other domains of psychosocial functioning (i.e., sociodemographic characteristics; informal social support and formal service utilization; perceived life stress; and resource loss). The present research was effective in uncovering important heterogeneity in psychological distress using a highly reliable and easily accessible measure of general psychological distress. Differentiating levels of psychological distress and associated patterns of psychosocial risk can be used to develop intervention strategies targeting the needs of different subgroups of women. Implications for treatment and future research are presented. PMID:25915692

Clustering of 770,000 genomes reveals post-colonial population structure of North America

NASA Astrophysics Data System (ADS)

Han, Eunjung; Carbonetto, Peter; Curtis, Ross E.; Wang, Yong; Granka, Julie M.; Byrnes, Jake; Noto, Keith; Kermany, Amir R.; Myres, Natalie M.; Barber, Mathew J.; Rand, Kristin A.; Song, Shiya; Roman, Theodore; Battat, Erin; Elyashiv, Eyal; Guturu, Harendra; Hong, Eurie L.; Chahine, Kenneth G.; Ball, Catherine A.

2017-02-01

Despite strides in characterizing human history from genetic polymorphism data, progress in identifying genetic signatures of recent demography has been limited. Here we identify very recent fine-scale population structure in North America from a network of over 500 million genetic (identity-by-descent, IBD) connections among 770,000 genotyped individuals of US origin. We detect densely connected clusters within the network and annotate these clusters using a database of over 20 million genealogical records. Recent population patterns captured by IBD clustering include immigrants such as Scandinavians and French Canadians; groups with continental admixture such as Puerto Ricans; settlers such as the Amish and Appalachians who experienced geographic or cultural isolation; and broad historical trends, including reduced north-south gene flow. Our results yield a detailed historical portrait of North America after European settlement and support substantial genetic heterogeneity in the United States beyond that uncovered by previous studies.

A characteristic length scale causes anomalous size effects and boundary programmability in mechanical metamaterials

NASA Astrophysics Data System (ADS)

Coulais, Corentin; Kettenis, Chris; van Hecke, Martin

2018-01-01

The architecture of mechanical metamaterials is designed to harness geometry, nonlinearity and topology to obtain advanced functionalities such as shape morphing, programmability and one-way propagation. Although a purely geometric framework successfully captures the physics of small systems under idealized conditions, large systems or heterogeneous driving conditions remain essentially unexplored. Here we uncover strong anomalies in the mechanics of a broad class of metamaterials, such as auxetics, shape changers or topological insulators; a non-monotonic variation of their stiffness with system size, and the ability of textured boundaries to completely alter their properties. These striking features stem from the competition between rotation-based deformations--relevant for small systems--and ordinary elasticity, and are controlled by a characteristic length scale which is entirely tunable by the architectural details. Our study provides new vistas for designing, controlling and programming the mechanics of metamaterials.

Clustering of 770,000 genomes reveals post-colonial population structure of North America

PubMed Central

Han, Eunjung; Carbonetto, Peter; Curtis, Ross E.; Wang, Yong; Granka, Julie M.; Byrnes, Jake; Noto, Keith; Kermany, Amir R.; Myres, Natalie M.; Barber, Mathew J.; Rand, Kristin A.; Song, Shiya; Roman, Theodore; Battat, Erin; Elyashiv, Eyal; Guturu, Harendra; Hong, Eurie L.; Chahine, Kenneth G.; Ball, Catherine A.

2017-01-01

Despite strides in characterizing human history from genetic polymorphism data, progress in identifying genetic signatures of recent demography has been limited. Here we identify very recent fine-scale population structure in North America from a network of over 500 million genetic (identity-by-descent, IBD) connections among 770,000 genotyped individuals of US origin. We detect densely connected clusters within the network and annotate these clusters using a database of over 20 million genealogical records. Recent population patterns captured by IBD clustering include immigrants such as Scandinavians and French Canadians; groups with continental admixture such as Puerto Ricans; settlers such as the Amish and Appalachians who experienced geographic or cultural isolation; and broad historical trends, including reduced north-south gene flow. Our results yield a detailed historical portrait of North America after European settlement and support substantial genetic heterogeneity in the United States beyond that uncovered by previous studies. PMID:28169989

Tunable Single-Cell Extraction for Molecular Analyses.

PubMed

Guillaume-Gentil, Orane; Grindberg, Rashel V; Kooger, Romain; Dorwling-Carter, Livie; Martinez, Vincent; Ossola, Dario; Pilhofer, Martin; Zambelli, Tomaso; Vorholt, Julia A

2016-07-14

Because of cellular heterogeneity, the analysis of endogenous molecules from single cells is of significant interest and has major implications. While micromanipulation or cell sorting followed by cell lysis is already used for subsequent molecular examinations, approaches to directly extract the content of living cells remain a challenging but promising alternative to achieving non-destructive sampling and cell-context preservation. Here, we demonstrate the quantitative extraction from single cells with spatiotemporal control using fluidic force microscopy. We further present a comprehensive analysis of the soluble molecules withdrawn from the cytoplasm or the nucleus, including the detection of enzyme activities and transcript abundances. This approach has uncovered the ability of cells to withstand extraction of up to several picoliters and opens opportunities to study cellular dynamics and cell-cell communication under physiological conditions at the single-cell level. Copyright © 2016 Elsevier Inc. All rights reserved.

Transcriptome Analysis at the Single-Cell Level Using SMART Technology.

PubMed

Fish, Rachel N; Bostick, Magnolia; Lehman, Alisa; Farmer, Andrew

2016-10-10

RNA sequencing (RNA-seq) is a powerful method for analyzing cell state, with minimal bias, and has broad applications within the biological sciences. However, transcriptome analysis of seemingly homogenous cell populations may in fact overlook significant heterogeneity that can be uncovered at the single-cell level. The ultra-low amount of RNA contained in a single cell requires extraordinarily sensitive and reproducible transcriptome analysis methods. As next-generation sequencing (NGS) technologies mature, transcriptome profiling by RNA-seq is increasingly being used to decipher the molecular signature of individual cells. This unit describes an ultra-sensitive and reproducible protocol to generate cDNA and sequencing libraries directly from single cells or RNA inputs ranging from 10 pg to 10 ng. Important considerations for working with minute RNA inputs are given. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Molecular pathology and genetics of gastrointestinal neuroendocrine tumours.

PubMed

Lewis, Mark A; Yao, James C

2014-02-01

Neuroendocrine tumours (NETs) of the luminal gastrointestinal tract and pancreas are increasing in incidence and prevalence. Prior assumptions about the benign nature of 'carcinoids' and the clinical importance of distinguishing functional vs. nonfunctional tumours are being overturned through greater understanding of disease behaviour and heterogeneity. This review highlights the most contemporary genetic and molecular insights into gastroenteropancreatic NETs. Biomarkers such as neuron-specific enolase or chromogranin A could be supplemented or supplanted by PCR-based analysis of NET genes detectable in the blood transcriptome. Conventional pathology, including Ki67 testing, could be enhanced with immunohistochemistry and exome analysis. Prognostic markers and/or putative therapeutic targets uncovered through recent studies include heparanase, Id, ATM, SRC, EGFR, hsp90 and PDGFR. After a long-standing paucity of options for conventional cytotoxic therapy, the comprehension and treatment of gastroenteropancreatic NETs has been enriched by advancements in taxonomy, molecular pathology and genetic/epigenetic testing.

Micro-navigation in complex periodic environments

NASA Astrophysics Data System (ADS)

Chamolly, Alexander; Ishikawa, Takuji; Lauga, Eric

2017-11-01

Natural and artificial small-scale swimmers may often self-propel in environments subject to complex geometrical constraints. While most past theoretical work on low-Reynolds number locomotion addressed idealised geometrical situations, not much is known on the motion of swimmers in heterogeneous environments. We investigate theoretically and numerically the behaviour of a single spherical micro-swimmer located in an infinite, periodic body-centred cubic lattice consisting of rigid inert spheres of the same size as the swimmer. We uncover a surprising and complex phase diagram of qualitatively different trajectories depending on the lattice packing density and swimming actuation strength. These results are then rationalised using hydrodynamic theory. In particular we show that the far-field nature of the swimmer (pusher vs. puller) governs the behaviour even at high volume fractions. ERC Grant PhyMeBa (682754, EL); JSPS Grant-in-Aid for Scientific Research (A) (17H00853, TI).

Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

PubMed Central

Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

2016-01-01

Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis. PMID:27048866

The Italian primary school-size distribution and the city-size: a complex nexus

NASA Astrophysics Data System (ADS)

Belmonte, Alessandro; di Clemente, Riccardo; Buldyrev, Sergey V.

2014-06-01

We characterize the statistical law according to which Italian primary school-size distributes. We find that the school-size can be approximated by a log-normal distribution, with a fat lower tail that collects a large number of very small schools. The upper tail of the school-size distribution decreases exponentially and the growth rates are distributed with a Laplace PDF. These distributions are similar to those observed for firms and are consistent with a Bose-Einstein preferential attachment process. The body of the distribution features a bimodal shape suggesting some source of heterogeneity in the school organization that we uncover by an in-depth analysis of the relation between schools-size and city-size. We propose a novel cluster methodology and a new spatial interaction approach among schools which outline the variety of policies implemented in Italy. Different regional policies are also discussed shedding lights on the relation between policy and geographical features.

Clustering of 770,000 genomes reveals post-colonial population structure of North America.

PubMed

Han, Eunjung; Carbonetto, Peter; Curtis, Ross E; Wang, Yong; Granka, Julie M; Byrnes, Jake; Noto, Keith; Kermany, Amir R; Myres, Natalie M; Barber, Mathew J; Rand, Kristin A; Song, Shiya; Roman, Theodore; Battat, Erin; Elyashiv, Eyal; Guturu, Harendra; Hong, Eurie L; Chahine, Kenneth G; Ball, Catherine A

2017-02-07

Despite strides in characterizing human history from genetic polymorphism data, progress in identifying genetic signatures of recent demography has been limited. Here we identify very recent fine-scale population structure in North America from a network of over 500 million genetic (identity-by-descent, IBD) connections among 770,000 genotyped individuals of US origin. We detect densely connected clusters within the network and annotate these clusters using a database of over 20 million genealogical records. Recent population patterns captured by IBD clustering include immigrants such as Scandinavians and French Canadians; groups with continental admixture such as Puerto Ricans; settlers such as the Amish and Appalachians who experienced geographic or cultural isolation; and broad historical trends, including reduced north-south gene flow. Our results yield a detailed historical portrait of North America after European settlement and support substantial genetic heterogeneity in the United States beyond that uncovered by previous studies.

Threshold Evaluation of Emergency Risk Communication for Health Risks Related to Hazardous Ambient Temperature.

PubMed

Liu, Yang; Hoppe, Brenda O; Convertino, Matteo

2018-04-10

Emergency risk communication (ERC) programs that activate when the ambient temperature is expected to cross certain extreme thresholds are widely used to manage relevant public health risks. In practice, however, the effectiveness of these thresholds has rarely been examined. The goal of this study is to test if the activation criteria based on extreme temperature thresholds, both cold and heat, capture elevated health risks for all-cause and cause-specific mortality and morbidity in the Minneapolis-St. Paul Metropolitan Area. A distributed lag nonlinear model (DLNM) combined with a quasi-Poisson generalized linear model is used to derive the exposure-response functions between daily maximum heat index and mortality (1998-2014) and morbidity (emergency department visits; 2007-2014). Specific causes considered include cardiovascular, respiratory, renal diseases, and diabetes. Six extreme temperature thresholds, corresponding to 1st-3rd and 97th-99th percentiles of local exposure history, are examined. All six extreme temperature thresholds capture significantly increased relative risks for all-cause mortality and morbidity. However, the cause-specific analyses reveal heterogeneity. Extreme cold thresholds capture increased mortality and morbidity risks for cardiovascular and respiratory diseases and extreme heat thresholds for renal disease. Percentile-based extreme temperature thresholds are appropriate for initiating ERC targeting the general population. Tailoring ERC by specific causes may protect some but not all individuals with health conditions exacerbated by hazardous ambient temperature exposure. © 2018 Society for Risk Analysis.

Mapping the Decadal Spatio-temporal Variation of Social Vulnerability to Hydro-climatic Extremes over India

NASA Astrophysics Data System (ADS)

H, V.; Karmakar, S.; Ghosh, S.

2015-12-01

Human induced global warming is unequivocal and observational studies shows that, this has led to increase in the intensity and frequency of hydro-climatic extremes, most importantly precipitation extreme, heat waves and drought; and also is expected to be increased in the future. The occurrence of these extremes have a devastating effects on nation's economy and on societal well-being. Previous studies on India provided the evidences of significant changes in the precipitation extreme from pre- to post-1950, with huge spatial heterogeneity; and projections of heat waves indicated that significant part of India will experience heat stress conditions in the future. Under these circumstance, it is necessary to develop a nation-wide social vulnerability map to scrutinize the adequacy of existing emergency management. Yet there has been no systematic past efforts on mapping social vulnerability to hydro-climatic extremes at nation-wide for India. Therefore, immediate efforts are required to quantify the social vulnerability, particularly developing country like India, where major transformations in demographic characteristics and development patterns are evident during past decades. In the present study, we perform a comprehensive spatio-temporal social vulnerability analysis by considering multiple sensitive indicators for three decades (1990-2010) which identifies the hot-spots, with higher vulnerability to hydro-climatic extremes. The population datasets are procured from Census of India and the meteorological datasets are obtained from India Meteorological Department (IMD). The study derives interesting results on decadal changes of spatial distribution of risk, considering social vulnerability and hazard to extremes.

Using extreme phenotype sampling to identify the rare causal variants of quantitative traits in association studies.

PubMed

Li, Dalin; Lewinger, Juan Pablo; Gauderman, William J; Murcray, Cassandra Elizabeth; Conti, David

2011-12-01

Variants identified in recent genome-wide association studies based on the common-disease common-variant hypothesis are far from fully explaining the hereditability of complex traits. Rare variants may, in part, explain some of the missing hereditability. Here, we explored the advantage of the extreme phenotype sampling in rare-variant analysis and refined this design framework for future large-scale association studies on quantitative traits. We first proposed a power calculation approach for a likelihood-based analysis method. We then used this approach to demonstrate the potential advantages of extreme phenotype sampling for rare variants. Next, we discussed how this design can influence future sequencing-based association studies from a cost-efficiency (with the phenotyping cost included) perspective. Moreover, we discussed the potential of a two-stage design with the extreme sample as the first stage and the remaining nonextreme subjects as the second stage. We demonstrated that this two-stage design is a cost-efficient alternative to the one-stage cross-sectional design or traditional two-stage design. We then discussed the analysis strategies for this extreme two-stage design and proposed a corresponding design optimization procedure. To address many practical concerns, for example measurement error or phenotypic heterogeneity at the very extremes, we examined an approach in which individuals with very extreme phenotypes are discarded. We demonstrated that even with a substantial proportion of these extreme individuals discarded, an extreme-based sampling can still be more efficient. Finally, we expanded the current analysis and design framework to accommodate the CMC approach where multiple rare-variants in the same gene region are analyzed jointly. © 2011 Wiley Periodicals, Inc.

Using Extreme Phenotype Sampling to Identify the Rare Causal Variants of Quantitative Traits in Association Studies

PubMed Central

Li, Dalin; Lewinger, Juan Pablo; Gauderman, William J.; Murcray, Cassandra Elizabeth; Conti, David

2014-01-01

Variants identified in recent genome-wide association studies based on the common-disease common-variant hypothesis are far from fully explaining the hereditability of complex traits. Rare variants may, in part, explain some of the missing hereditability. Here, we explored the advantage of the extreme phenotype sampling in rare-variant analysis and refined this design framework for future large-scale association studies on quantitative traits. We first proposed a power calculation approach for a likelihood-based analysis method. We then used this approach to demonstrate the potential advantages of extreme phenotype sampling for rare variants. Next, we discussed how this design can influence future sequencing-based association studies from a cost-efficiency (with the phenotyping cost included) perspective. Moreover, we discussed the potential of a two-stage design with the extreme sample as the first stage and the remaining nonextreme subjects as the second stage. We demonstrated that this two-stage design is a cost-efficient alternative to the one-stage cross-sectional design or traditional two-stage design. We then discussed the analysis strategies for this extreme two-stage design and proposed a corresponding design optimization procedure. To address many practical concerns, for example measurement error or phenotypic heterogeneity at the very extremes, we examined an approach in which individuals with very extreme phenotypes are discarded. We demonstrated that even with a substantial proportion of these extreme individuals discarded, an extreme-based sampling can still be more efficient. Finally, we expanded the current analysis and design framework to accommodate the CMC approach where multiple rare-variants in the same gene region are analyzed jointly. PMID:21922541

Timing of floods in southeastern China: Seasonal properties and potential causes

NASA Astrophysics Data System (ADS)

Zhang, Qiang; Gu, Xihui; Singh, Vijay P.; Shi, Peijun; Luo, Ming

2017-09-01

Flood hazards and flood risks in southeastern China have been causing increasing concerns due to dense population and highly-developed economy. This study attempted to address changes of seasonality, timing of peak floods and variability of occurrence date of peak floods using circular statistical methods and the modified Mann-Kendall trend detection method. The causes of peak flood changes were also investigated. Results indicated that: (1) floods were subject to more seasonality and temporal clustering when compared to precipitation extremes. However, seasonality of floods and extreme precipitation was subject to spatial heterogeneity in northern Guangdong. Similar changing patterns of peak floods and extreme precipitation were found in coastal regions; (2) significant increasing/decreasing seasonality, but no confirmed spatial patterns, were observed for peak floods and extreme precipitation. Peak floods in northern Guangdong province had decreasing variability, but had larger variability in coastal regions; (3) tropical cyclones had remarkable impacts on extreme precipitation changes in coastal regions of southeastern China, and peak floods as well. The landfalling of tropical cyclones was decreasing and concentrated during June-September; this is the major reason for earlier but enhanced seasonality of peak floods in coastal regions. This study sheds new light on flood behavior in coastal regions in a changing environment.

Variability and Extremes of Precipitation in the Global Climate as Determined by the 25-Year GEWEX/GPCP Data Set

NASA Technical Reports Server (NTRS)

Adler, R. F.; Gu, G.; Curtis, S.; Huffman, G. J.; Bolvin, D. T.; Nelkin, E. J.

2005-01-01

The Global Precipitation Climatology Project (GPCP) 25-year precipitation data set is used to evaluate the variability and extremes on global and regional scales. The variability of precipitation year-to-year is evaluated in relation to the overall lack of a significant global trend and to climate events such as ENSO and volcanic eruptions. The validity of conclusions and limitations of the data set are checked by comparison with independent data sets (e.g., TRMM). The GPCP data set necessarily has a heterogeneous time series of input data sources, so part of the assessment described above is to test the initial results for potential influence by major data boundaries in the record. Regional trends, or inter-decadal changes, are also analyzed to determine validity and correlation with other long-term data sets related to the hydrological cycle (e.g., clouds and ocean surface fluxes). Statistics of extremes (both wet and dry) are analyzed at the monthly time scale for the 25 years. A preliminary result of increasing frequency of extreme monthly values will be a focus to determine validity. Daily values for an eight-year are also examined for variation in extremes and compared to the longer monthly-based study.

Terrestrial habitat selection and strong density-dependent mortality in recently metamorphosed amphibians.

PubMed

Patrick, David A; Harper, Elizabeth B; Hunter, Malcolm L; Calhoun, Aram J K

2008-09-01

To predict the effects of terrestrial habitat change on amphibian populations, we need to know how amphibians respond to habitat heterogeneity, and whether habitat choice remains consistent throughout the life-history cycle. We conducted four experiments to evaluate how the spatial distribution of juvenile wood frogs, Rana sylvatica (including both overall abundance and localized density), was influenced by habitat choice and habitat structure, and how this relationship changed with spatial scale and behavioral phase. The four experiments included (1) habitat manipulation on replicated 10-ha landscapes surrounding breeding pools; (2) short-term experiments with individual frogs emigrating through a manipulated landscape of 1 m wide hexagonal patches; and habitat manipulations in (3) small (4-m2); and (4) large (100-m2) enclosures with multiple individuals to compare behavior both during and following emigration. The spatial distribution of juvenile wood frogs following emigration resulted from differences in the scale at which juvenile amphibians responded to habitat heterogeneity during active vs. settled behavioral phases. During emigration, juvenile wood frogs responded to coarse-scale variation in habitat (selection between 2.2-ha forest treatments) but not to fine-scale variation. After settling, however, animals showed habitat selection at much smaller scales (2-4 m2). This resulted in high densities of animals in small patches of suitable habitat where they experienced rapid mortality. No evidence of density-dependent habitat selection was seen, with juveniles typically choosing to remain at extremely high densities in high-quality habitat, rather than occupying low-quality habitat. These experiments demonstrate how prediction of the terrestrial distribution of juvenile amphibians requires understanding of the complex behavioral responses to habitat heterogeneity. Understanding these patterns is important, given that human alterations to amphibian habitats may generate extremely high densities of animals, resulting in high density-dependent mortality.

Advanced Artificial Dielectric Materials for Millimeter Wavelength Applications.

DTIC Science & Technology

1984-10-26

extreme, it reaches a finite value, ot’ = - 3/8ir, corresponding to the magnetic behavior of a superconducting sphere [201. E 0.01 10 / - +.c I/LIMIT...dispersion of small magnetic particles, one must proceed carefully in accounting for the various demagnetizing effects, internal and external fields, etc...rum!:er, * ’B0 GOUPSUB OR Artificial Dielectrics, Induced Magnetic Permeability, Properties of’ Heterogeneous Media. Fine Powder Preparation

Climate and topography explain range sizes of terrestrial vertebrates

NASA Astrophysics Data System (ADS)

Li, Yiming; Li, Xianping; Sandel, Brody; Blank, David; Liu, Zetian; Liu, Xuan; Yan, Shaofei

2016-05-01

Identifying the factors that influence range sizes of species provides important insight into the distribution of biodiversity, and is crucial for predicting shifts in species ranges in response to climate change. Current climate (for example, climate variability and climate extremes), long-term climate change, evolutionary age, topographic heterogeneity, land area and species traits such as physiological thermal limits, dispersal ability, annual fecundity and body size have been shown to influence range size. Yet, few studies have examined the generality of each of these factors among different taxa, or have simultaneously evaluated the strength of relationships between range size and these factors at a global scale. We quantify contributions of these factors to range sizes of terrestrial vertebrates (mammals, birds and reptiles) at a global scale. We found that large-ranged species experience greater monthly extremes of maximum or minimum temperature within their ranges, or occur in areas with higher long-term climate velocity and lower topographic heterogeneity or lower precipitation seasonality. Flight ability, body mass and continent width are important only for particular taxa. Our results highlight the importance of climate and topographic context in driving range size variation. The results suggest that small-range species may be vulnerable to climate change and should be the focus of conservation efforts.

Lack of access to chemotherapy for colon cancer: multiplicative disadvantage of being extremely poor, inadequately insured and African American.

PubMed

Gorey, Kevin M; Haji-Jama, Sundus; Bartfay, Emma; Luginaah, Isaac N; Wright, Frances C; Kanjeekal, Sindu M

2014-03-22

Despite evidence of chemotherapy's ability to cure or comfort those with colon cancer, nearly half of such Americans do not receive it. African Americans (AA) seem particularly disadvantaged. An ethnicity by poverty by health insurance interaction was hypothesized such that the multiplicative disadvantage of being extremely poor and inadequately insured is worse for AAs than for non-Hispanic white Americans (NHWA). California registry data were analyzed for 459 AAs and 3,001 NHWAs diagnosed with stage II to IV colon cancer between 1996 and 2000 and followed until 2011. Socioeconomic data from the 2000 census categorized neighborhoods: extremely poor (≥ 30% of households poor), middle (5-29% poor) and low poverty (< 5% poor). Participants were randomly selected from these poverty strata. Primary health insurers were Medicaid, Medicare, private or none. Chemotherapy rates were age and stage-adjusted and comparisons used standardized rate ratios (RR). Logistic and Cox regressions, respectively, modeled chemotherapy receipt and long term survival. A significant 3-way ethnicity by poverty by health insurance interaction effect on chemotherapy receipt was observed. Among those who did not live in extremely poor neighborhoods and were adequately insured privately or by Medicare, chemotherapy rates did not differ significantly between AAs (37.7%) and NHWAs (39.5%). Among those who lived in extremely poor neighborhoods and were inadequately insured by Medicaid or uninsured, AAs (14.6%) were nearly 60% less likely to receive chemotherapy than were NHWAs (25.5%, RR = 0.41). When the 3-way interaction effect as well as the main effects of poverty, health insurance and chemotherapy was accounted for, survival rates of AAs and NHWAs were the same. The multiplicative barrier to colon cancer care that results from being extremely poor and inadequately insured is worse for AAs than it is for NHWAs. AAs are more prevalently poor, inadequately insured, and have fewer assets so they are probably less able to absorb the indirect and direct, but uncovered, costs of colon cancer care. Policy makers ought to be cognizant of these factors as they implement the Affordable Care Act and consider future health care reforms.

Partially covered metal stents have longer patency than uncovered and fully covered metal stents in the management of distal malignant biliary obstruction: a retrospective study.

PubMed

Yokota, Yudai; Fukasawa, Mitsuharu; Takano, Shinichi; Kadokura, Makoto; Shindo, Hiroko; Takahashi, Ei; Hirose, Sumio; Kawakami, Satoshi; Fukasawa, Yoshimitsu; Sato, Tadashi; Enomoto, Nobuyuki

2017-10-11

Self-expandable metal stents (SEMSs) are widely used for malignant biliary obstructions. Nitinol-covered SEMSs have been developed to improve stent patency. Currently, SEMSs may be uncovered, partially covered, or fully covered; however, there is no consensus on the best stent type for the management of malignant distal biliary obstruction (MDBO). Patients with unresectable MDBO receiving SEMS (Wallflex™) were retrospectively analyzed. Time to recurrent biliary obstruction (TRBO) and survival time were compared among the three types of SEMSs. Univariate and multivariate analyses were performed to identify risk factors for stent dysfunction. In total, 101 patients received SEMSs for unresectable MDBO (44 uncovered, 28 partially covered, and 29 fully covered SEMSs). Median survival time was 200, 168, and 276 days in the uncovered, partially covered, and fully covered SEMSs groups, respectively. There were no differences in survival among the three groups. Median TRBO was 199, 444, and 194 days in the uncovered, partially covered, and fully covered SEMSs groups, respectively. Partially covered SEMSs had longer TRBO than uncovered (p = 0.013) and fully covered (p = 0.010) SEMSs. Tumor ingrowth occurred only with uncovered SEMSs and stent migration occurred only with fully covered SEMSs. Multivariate analyses confirmed that partially covered SEMSs have lower risk of dysfunction. Partially covered SEMSs with a proximal uncovered flared end have longer patency than uncovered and fully covered SEMSs by preventing tumor ingrowth and stent migration.

Single crystal growth of Ga3Ni2 by the Czochralski method

NASA Astrophysics Data System (ADS)

Wencka, Magdalena; Pillaca, Mirtha; Gille, Peter

2016-09-01

Intermetallic compounds have proved to be interesting alternatives to heterogeneous catalysts prepared from pure noble metals or their alloys. As to study their intrinsic properties, to determine the crystalline structures of specific surfaces and finally to understand elementary processes of heterogeneous catalysis, single crystals of these intermetallics are needed. Inspired by the recent discovery of Ga-Ni catalysts for carbon dioxide reduction to methanol, we have grown for the first time cm3-size single crystals of trigonal Ga3Ni2. We report in detail on the synthesis and Czochralski growth from high-temperature solution using Ga as native solvent. Inclusion formation of Ga-rich fluid proved to be the most severe problem that was minimized by using an extremely low pulling rate down to 25 μm/h.

Mechanistic comparisons of functional domains across pediatric and adult bipolar disorder highlight similarities, as well as differences, influenced by the developing brain.

PubMed

Wegbreit, Ezra; Pavuluri, Mani

2012-01-01

Recent neuroimaging studies have uncovered much about the specific neural deficits in adult bipolar disorder (ABD), but despite promising results, neuroimaging research for pediatric bipolar disorder (PBD) is still developing. The neuroimaging literature is highly heterogeneous, varying in the paradigms used and in participants' mood states and medication status. Despite this variability, several dominant patterns emerge. In response to emotional stimuli, both ABD and PBD show limbic hyperactivity coupled with hypoactivity in ventral prefrontal emotion regulation systems. This pattern occurred most robustly in response to negative incidental stimuli and was especially apparent in manic PBD. ABD showed more variability in ventral prefrontal activity, possibly due to maturational and medication factors. On numerous cognitive paradigms, PBD showed dorsal prefrontal hypoactivity linked to ventral dysfunction, whereas ABD showed compensatory frontal, parietal, and temporal activity with paradigm-specific variations. In emotion-cognition interaction paradigms, patients show dysregulation in regions interfacing between cognitive and emotional brain systems (e.g., ventral prefrontal and cingulate cortices), which expend extra effort to process emotional stimuli effectively and recruit additional posterior attention systems to cope with affective instability. In addition, novel functional connectivity techniques have uncovered connectivity deficits between frontal and limbic regions in ABD and PBD at rest and during active emotional and cognitive tasks. Finally, the neuroimaging literature currently lacks cross-sectional studies comparing PBD with ABD and longitudinal studies following children and adolescents with BD into adulthood. Such studies would provide important insights into patients' prognosis and would determine targets for early interventions in the evolving illness diathesis.

Step selection techniques uncover the environmental predictors of space use patterns in flocks of Amazonian birds.

PubMed

Potts, Jonathan R; Mokross, Karl; Stouffer, Philip C; Lewis, Mark A

2014-12-01

Understanding the behavioral decisions behind animal movement and space use patterns is a key challenge for behavioral ecology. Tools to quantify these patterns from movement and animal-habitat interactions are vital for transforming ecology into a predictive science. This is particularly important in environments undergoing rapid anthropogenic changes, such as the Amazon rainforest, where animals face novel landscapes. Insectivorous bird flocks are key elements of avian biodiversity in the Amazonian ecosystem. Therefore, disentangling and quantifying the drivers behind their movement and space use patterns is of great importance for Amazonian conservation. We use a step selection function (SSF) approach to uncover environmental drivers behind movement choices. This is used to construct a mechanistic model, from which we derive predicted utilization distributions (home ranges) of flocks. We show that movement decisions are significantly influenced by canopy height and topography, but depletion and renewal of resources do not appear to affect movement significantly. We quantify the magnitude of these effects and demonstrate that they are helpful for understanding various heterogeneous aspects of space use. We compare our results to recent analytic derivations of space use, demonstrating that the analytic approximation is only accurate when assuming that there is no persistence in the animals' movement. Our model can be translated into other environments or hypothetical scenarios, such as those given by proposed future anthropogenic actions, to make predictions of spatial patterns in bird flocks. Furthermore, our approach is quite general, so could potentially be used to understand the drivers of movement and spatial patterns for a wide variety of animal communities.

Parallel Coding of First- and Second-Order Stimulus Attributes by Midbrain Electrosensory Neurons

PubMed Central

McGillivray, Patrick; Vonderschen, Katrin; Fortune, Eric S.; Chacron, Maurice J.

2015-01-01

Natural stimuli often have time-varying first-order (i.e., mean) and second-order (i.e., variance) attributes that each carry critical information for perception and can vary independently over orders of magnitude. Experiments have shown that sensory systems continuously adapt their responses based on changes in each of these attributes. This adaptation creates ambiguity in the neural code as multiple stimuli may elicit the same neural response. While parallel processing of first- and second-order attributes by separate neural pathways is sufficient to remove this ambiguity, the existence of such pathways and the neural circuits that mediate their emergence have not been uncovered to date. We recorded the responses of midbrain electrosensory neurons in the weakly electric fish Apteronotus leptorhynchus to stimuli with first- and second-order attributes that varied independently in time. We found three distinct groups of midbrain neurons: the first group responded to both first- and second-order attributes, the second group responded selectively to first-order attributes, and the last group responded selectively to second-order attributes. In contrast, all afferent hindbrain neurons responded to both first- and second-order attributes. Using computational analyses, we show how inputs from a heterogeneous population of ON- and OFF-type afferent neurons are combined to give rise to response selectivity to either first- or second-order stimulus attributes in midbrain neurons. Our study thus uncovers, for the first time, generic and widely applicable mechanisms by which parallel processing of first- and second-order stimulus attributes emerges in the brain. PMID:22514313

Step selection techniques uncover the environmental predictors of space use patterns in flocks of Amazonian birds

PubMed Central

Potts, Jonathan R; Mokross, Karl; Stouffer, Philip C; Lewis, Mark A

2014-01-01

Understanding the behavioral decisions behind animal movement and space use patterns is a key challenge for behavioral ecology. Tools to quantify these patterns from movement and animal–habitat interactions are vital for transforming ecology into a predictive science. This is particularly important in environments undergoing rapid anthropogenic changes, such as the Amazon rainforest, where animals face novel landscapes. Insectivorous bird flocks are key elements of avian biodiversity in the Amazonian ecosystem. Therefore, disentangling and quantifying the drivers behind their movement and space use patterns is of great importance for Amazonian conservation. We use a step selection function (SSF) approach to uncover environmental drivers behind movement choices. This is used to construct a mechanistic model, from which we derive predicted utilization distributions (home ranges) of flocks. We show that movement decisions are significantly influenced by canopy height and topography, but depletion and renewal of resources do not appear to affect movement significantly. We quantify the magnitude of these effects and demonstrate that they are helpful for understanding various heterogeneous aspects of space use. We compare our results to recent analytic derivations of space use, demonstrating that the analytic approximation is only accurate when assuming that there is no persistence in the animals' movement. Our model can be translated into other environments or hypothetical scenarios, such as those given by proposed future anthropogenic actions, to make predictions of spatial patterns in bird flocks. Furthermore, our approach is quite general, so could potentially be used to understand the drivers of movement and spatial patterns for a wide variety of animal communities. PMID:25558353

Circuits of cancer drivers revealed by convergent misregulation of transcription factor targets across tumor types.

PubMed

Gonzalez-Perez, Abel

2016-01-20

Large tumor genome sequencing projects have now uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies. One of the main challenges emerging from this catalog of drivers is how to make sense of their heterogeneity in most cancer types. This is key not only to understand how carcinogenesis appears and develops in these malignancies to be able to early diagnose them, but also to open up the possibility to employ therapeutic strategies targeting a driver protein to counteract the alteration of another connected driver. Here, I focus on driver transcription factors and their connection to tumorigensis in several tumor types through the alteration of the expression of their targets. First, I explore their involvement in tumorigenesis as mutational drivers in 28 different tumor types. Then, I collect a list of downstream targets of the all driver transcription factors (TFs), and identify which of them exhibit a differential expression upon alterations of driver transcription factors. I identify the subset of targets of each TF most likely mediating the tumorigenic effect of their driver alterations in each tumor type, and explore their overlap. Furthermore, I am able to identify other driver genes that cause tumorigenesis through the alteration of very similar sets of targets. I thus uncover these circuits of connected drivers which cause tumorigenesis through the perturbation of overlapping cellular pathways in a pan-cancer manner across 15 malignancies. The systematic detection of these circuits may be key to propose novel therapeutic strategies indirectly targeting driver alterations in tumors.

A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.

PubMed

Lange, L; Pagnamenta, A T; Lise, S; Clasper, S; Stewart, H; Akha, E S; Quaghebeur, G; Knight, S J L; Keays, D A; Taylor, J C; Kini, U

2016-09-01

Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome. © 2016 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An emotional contagion model for heterogeneous social media with multiple behaviors

NASA Astrophysics Data System (ADS)

Xiong, Xi; Li, Yuanyuan; Qiao, Shaojie; Han, Nan; Wu, Yue; Peng, Jing; Li, Binyong

2018-01-01

The emotion varies and propagates with the spatial and temporal information of individuals through social media, which uncovers several interaction mechanisms and features the community structure in order to facilitate individuals' communication and emotional contagion in social networks. Aiming to show the detailed process and characteristics of emotional contagion within social media, we propose an emotional independent cascade model in which individual emotion can affect the subsequent emotion of his/her friends. The transmissibility is introduced to measure the capability of propagating emotion with respect to an individual in social networks. By analyzing the patterns of emotional contagion on Twitter data, we find that the value of transmissibility differs on different layers and on different community structures. Extensive experiments were conducted and the results reveal that, the polar emotion of hub users can lead to the disappearance of opposite emotion, and the transmissibility makes no sense. The final emotional distribution depends on the initial emotional distribution and the transmissibilities. Individuals from a small community are more likely to change their mood by the influence of community leaders. In addition, we compared the proposed model with two other models, the emotion-based spreader-ignorant-stifler model and the standard independent cascade model. The results demonstrate that the proposed model can reflect the real-world situation of emotional contagion for heterogeneous social media while the computational complexities of all these three models are similar.

Emergence of energy dependence in the fragmentation of heterogeneous materials

NASA Astrophysics Data System (ADS)

Pál, Gergő; Varga, Imre; Kun, Ferenc

2014-12-01

The most important characteristics of the fragmentation of heterogeneous solids is that the mass (size) distribution of pieces is described by a power law functional form. The exponent of the distribution displays a high degree of universality depending mainly on the dimensionality and on the brittle-ductile mechanical response of the system. Recently, experiments and computer simulations have reported an energy dependence of the exponent increasing with the imparted energy. These novel findings question the phase transition picture of fragmentation phenomena, and have also practical importance for industrial applications. Based on large scale computer simulations here we uncover a robust mechanism which leads to the emergence of energy dependence in fragmentation processes resolving controversial issues on the problem: studying the impact induced breakup of platelike objects with varying thickness in three dimensions we show that energy dependence occurs when a lower dimensional fragmenting object is embedded into a higher dimensional space. The reason is an underlying transition between two distinct fragmentation mechanisms controlled by the impact velocity at low plate thicknesses, while it is hindered for three-dimensional bulk systems. The mass distributions of the subsets of fragments dominated by the two cracking mechanisms proved to have an astonishing robustness at all plate thicknesses, which implies that the nonuniversality of the complete mass distribution is the consequence of blending the contributions of universal partial processes.

From "cracking the orthographic code" to "playing with language": toward a usage-based foundation of the reading process.

PubMed

Wallot, Sebastian

2014-01-01

The empirical study of reading dates back more than 125 years. But despite this long tradition, the scientific understanding of reading has made rather heterogeneous progress: many factors that influence the process of text reading have been uncovered, but theoretical explanations remain fragmented; no general theory pulls together the diverse findings. A handful of scholars have noted that properties thought to be at the core of the reading process do not actually generalize across different languages or from situations single-word reading to connected text reading. Such observations cast doubt on many of the traditional conceptions about reading. In this article, I suggest that the observed heterogeneity in the research is due to misguided conceptions about the reading process. Particularly problematic are the unrefined notions about meaning which undergird many reading theories: most psychological theories of reading implicitly assume a kind of elemental token semantics, where words serve as stable units of meaning in a text. This conception of meaning creates major conceptual problems. As an alternative, I argue that reading shoud be rather understood as a form of language use, which circumvents many of the conceptual problems and connects reading to a wider range of linguistic communication. Finally, drawing from Wittgenstein, the concept of "language games" is outlined as an approach to language use that can be operationalized scientifically to provide a new foundation for reading research.

SU-E-T-371: Evaluating the Convolution Algorithm of a Commercially Available Radiosurgery Irradiator Using a Novel Phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cates, J; Drzymala, R

2015-06-15

Purpose: The purpose of this study was to develop and use a novel phantom to evaluate the accuracy and usefulness of the Leskell Gamma Plan convolution-based dose calculation algorithm compared with the current TMR10 algorithm. Methods: A novel phantom was designed to fit the Leskell Gamma Knife G Frame which could accommodate various materials in the form of one inch diameter, cylindrical plugs. The plugs were split axially to allow EBT2 film placement. Film measurements were made during two experiments. The first utilized plans generated on a homogeneous acrylic phantom setup using the TMR10 algorithm, with various materials inserted intomore » the phantom during film irradiation to assess the effect on delivered dose due to unplanned heterogeneities upstream in the beam path. The second experiment utilized plans made on CT scans of different heterogeneous setups, with one plan using the TMR10 dose calculation algorithm and the second using the convolution-based algorithm. Materials used to introduce heterogeneities included air, LDPE, polystyrene, Delrin, Teflon, and aluminum. Results: The data shows that, as would be expected, having heterogeneities in the beam path does induce dose delivery error when using the TMR10 algorithm, with the largest errors being due to the heterogeneities with electron densities most different from that of water, i.e. air, Teflon, and aluminum. Additionally, the Convolution algorithm did account for the heterogeneous material and provided a more accurate predicted dose, in extreme cases up to a 7–12% improvement over the TMR10 algorithm. The convolution algorithm expected dose was accurate to within 3% in all cases. Conclusion: This study proves that the convolution algorithm is an improvement over the TMR10 algorithm when heterogeneities are present. More work is needed to determine what the heterogeneity size/volume limits are where this improvement exists, and in what clinical and/or research cases this would be relevant.« less

Intermediate disturbance in experimental landscapes improves persistence of beetle metapopulations.

PubMed

Govindan, Byju N; Feng, Zhilan; DeWoody, Yssa D; Swihart, Robert K

2015-03-01

Human-dominated landscapes often feature patches that fluctuate in suitability through space and time, but there is little experimental evidence relating the consequences of dynamic patches for species persistence. We used a spatially and temporally dynamic metapopulation model to assess and compare metapopulation capacity and persistence for red flour beetles (Tribolium castaneum) in experimental landscapes differentiated by resource structure, patch dynamics (destruction and restoration), and connectivity. High connectivity increased the colonization rate of beetles, but this effect was less pronounced in heterogeneous relative to homogeneous landscapes. Higher connectivity and faster patch dynamics increased extinction rates in landscapes. Lower connectivity promoted density-dependent emigration. Heterogeneous landscapes containing patches of different carrying capacity enhanced landscape-level occupancy probability. The highest metapopulation capacity and persistence was observed in landscapes with heterogeneous patches, low connectivity, and slow patch dynamics. Control landscapes with no patch dynamics exhibited rapid declines in abundance and approached extinction due to increased adult mortality in the matrix, higher pupal cannibalism by adults, and extremely low rates of exchange between remaining habitable patches. Our results highlight the role of intermediate patch dynamics, intermediate connectivity, and the nature of density dependence of emigration for persistence of species in heterogeneous landscapes. Our results also demonstrate the importance of incorporating local dynamics into the estimation of metapopulation capacity for conservation planning.

Heterogeneous Diels–Alder catalysis for biomass-derived aromatic compounds

DOE PAGES

Settle, Amy E.; Berstis, Laura; Rorrer, Nicholas A.; ...

2017-05-17

In this tutorial review, we provide an overview of heterogeneous Diels–Alder catalysis for the production of lignocellulosic biomass-derived aromatic compounds. Diels–Alder reactions afford an extremely selective and efficient route for carbon–carbon cycloadditions to produce intermediates that can readily undergo subsequent dehydration or dehydrogenation reactions for aromatization. As a result, catalysis of Diels–Alder reactions with biomass-derived dienes and dienophiles has seen a growth of interest in recent years; however, significant opportunities remain to (i) tailor heterogeneous catalyst materials for tandem Diels–Alder and aromatization reactions, and (ii) utilize biomass-derived dienes and dienophiles to access both conventional and novel aromatic monomers. As such,more » this review discusses the mechanistic aspects of Diels–Alder reactions from both an experimental and computational perspective, as well as the synergy of Brønsted–Lewis acid catalysts to facilitate tandem Diels–Alder and aromatization reactions. Heterogeneous catalyst design strategies for Diels–Alder reactions are reviewed for two exemplary solid acid catalysts, zeolites and polyoxometalates, and recent efforts for targeting direct replacement aromatic monomers from biomass are summarized. In conclusion, we point out important research directions for progressing Diels–Alder catalysis to target novel, aromatic monomers with chemical functionality that enables new properties compared to monomers that are readily accessible from petroleum.« less

Where we stand, where we are moving: Surveying computational techniques for identifying miRNA genes and uncovering their regulatory role.

PubMed

Kleftogiannis, Dimitrios; Korfiati, Aigli; Theofilatos, Konstantinos; Likothanassis, Spiros; Tsakalidis, Athanasios; Mavroudi, Seferina

2013-06-01

Traditional biology was forced to restate some of its principles when the microRNA (miRNA) genes and their regulatory role were firstly discovered. Typically, miRNAs are small non-coding RNA molecules which have the ability to bind to the 3'untraslated region (UTR) of their mRNA target genes for cleavage or translational repression. Existing experimental techniques for their identification and the prediction of the target genes share some important limitations such as low coverage, time consuming experiments and high cost reagents. Hence, many computational methods have been proposed for these tasks to overcome these limitations. Recently, many researchers emphasized on the development of computational approaches to predict the participation of miRNA genes in regulatory networks and to analyze their transcription mechanisms. All these approaches have certain advantages and disadvantages which are going to be described in the present survey. Our work is differentiated from existing review papers by updating the methodologies list and emphasizing on the computational issues that arise from the miRNA data analysis. Furthermore, in the present survey, the various miRNA data analysis steps are treated as an integrated procedure whose aims and scope is to uncover the regulatory role and mechanisms of the miRNA genes. This integrated view of the miRNA data analysis steps may be extremely useful for all researchers even if they work on just a single step. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison between uncovered and covered self-expandable metal stent placement in malignant duodenal obstruction.

PubMed

Kim, Ji Won; Jeong, Ji Bong; Lee, Kook Lae; Kim, Byeong Gwan; Ahn, Dong Won; Lee, Jae Kyung; Kim, Su Hwan

2015-02-07

To compare the clinical outcomes of uncovered and covered self-expandable metal stent placements in patients with malignant duodenal obstruction. A total of 67 patients were retrospectively enrolled from January 2003 to June 2013. All patients had symptomatic obstruction characterized by nausea, vomiting, reduced oral intake, and weight loss. The exclusion criteria included asymptomatic duodenal obstruction, perforation or peritonitis, concomitant small bowel obstruction, or duodenal obstruction caused by benign strictures. The technical and clinical success rate, complication rate, and stent patency were compared according to the placement of uncovered (n = 38) or covered (n = 29) stents. The technical and clinical success rates did not differ between the uncovered and covered stent groups (100% vs 96.6% and 89.5% vs 82.8%). There were no differences in the overall complication rates between the uncovered and covered stent groups (31.6% vs 41.4%). However, stent migration occurred more frequently with covered than uncovered stents [20.7% (6/29) vs 0% (0/38), P < 0.05]. Moreover, the overall cumulative median duration of stent patency was longer in uncovered than in covered stents [251 d (95%CI: 149.8 d-352.2 d) vs 139 d (95%CI: 45.5 d-232.5 d), P < 0.05 by log-rank test] The overall cumulative median survival period was not different between the uncovered stent (70 d) and covered stent groups (60 d). Uncovered stents may be preferable in malignant duodenal obstruction because of their greater resistance to stent migration and longer stent patency than covered stents.

Comparison between uncovered and covered self-expandable metal stent placement in malignant duodenal obstruction

PubMed Central

Kim, Ji Won; Jeong, Ji Bong; Lee, Kook Lae; Kim, Byeong Gwan; Ahn, Dong Won; Lee, Jae Kyung; Kim, Su Hwan

2015-01-01

AIM: To compare the clinical outcomes of uncovered and covered self-expandable metal stent placements in patients with malignant duodenal obstruction. METHODS: A total of 67 patients were retrospectively enrolled from January 2003 to June 2013. All patients had symptomatic obstruction characterized by nausea, vomiting, reduced oral intake, and weight loss. The exclusion criteria included asymptomatic duodenal obstruction, perforation or peritonitis, concomitant small bowel obstruction, or duodenal obstruction caused by benign strictures. The technical and clinical success rate, complication rate, and stent patency were compared according to the placement of uncovered (n = 38) or covered (n = 29) stents. RESULTS: The technical and clinical success rates did not differ between the uncovered and covered stent groups (100% vs 96.6% and 89.5% vs 82.8%). There were no differences in the overall complication rates between the uncovered and covered stent groups (31.6% vs 41.4%). However, stent migration occurred more frequently with covered than uncovered stents [20.7% (6/29) vs 0% (0/38), P < 0.05]. Moreover, the overall cumulative median duration of stent patency was longer in uncovered than in covered stents [251 d (95%CI: 149.8 d-352.2 d) vs 139 d (95%CI: 45.5 d-232.5 d), P < 0.05 by log-rank test] The overall cumulative median survival period was not different between the uncovered stent (70 d) and covered stent groups (60 d). CONCLUSION: Uncovered stents may be preferable in malignant duodenal obstruction because of their greater resistance to stent migration and longer stent patency than covered stents. PMID:25663777

A characterization of workflow management systems for extreme-scale applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferreira da Silva, Rafael; Filgueira, Rosa; Pietri, Ilia

We present that the automation of the execution of computational tasks is at the heart of improving scientific productivity. Over the last years, scientific workflows have been established as an important abstraction that captures data processing and computation of large and complex scientific applications. By allowing scientists to model and express entire data processing steps and their dependencies, workflow management systems relieve scientists from the details of an application and manage its execution on a computational infrastructure. As the resource requirements of today’s computational and data science applications that process vast amounts of data keep increasing, there is a compellingmore » case for a new generation of advances in high-performance computing, commonly termed as extreme-scale computing, which will bring forth multiple challenges for the design of workflow applications and management systems. This paper presents a novel characterization of workflow management systems using features commonly associated with extreme-scale computing applications. We classify 15 popular workflow management systems in terms of workflow execution models, heterogeneous computing environments, and data access methods. Finally, the paper also surveys workflow applications and identifies gaps for future research on the road to extreme-scale workflows and management systems.« less

Extremely Severe Space Weather and Geomagnetically Induced Currents in Regions with Locally Heterogeneous Ground Resistivity

NASA Technical Reports Server (NTRS)

Fujita, Shigeru; Kataoka, Ryuho; Pulkkinen, Antti; Watari, Shinichi

2016-01-01

Large geomagnetically induced currents (GICs) triggered by extreme space weather events are now regarded as one of the serious natural threats to the modern electrified society. The risk is described in detail in High-Impact, Low-Frequency Event Risk, A Jointly-Commissioned Summary Report of the North American Electric Reliability Corporation and the US Department of Energy's November 2009 Workshop, June 2010. For example, the March 13-14,1989 storm caused a large-scale blackout affecting about 6 million people in Quebec, Canada, and resulting in substantial economic losses in Canada and the USA (Bolduc 2002). Therefore, European and North American nations have invested in GIC research such as the Solar Shield project in the USA (Pulkkinen et al. 2009, 2015a). In 2015, the Japanese government (Ministry of Economy, Trade and Industry, METI) acknowledged the importance of GIC research in Japan. After reviewing the serious damages caused by the 2011 Tohoku-Oki earthquake, METI recognized the potential risk to the electric power grid posed by extreme space weather. During extreme events, GICs can be concerning even in mid- and low-latitude countries and have become a global issue.

A characterization of workflow management systems for extreme-scale applications

DOE PAGES

Ferreira da Silva, Rafael; Filgueira, Rosa; Pietri, Ilia; ...

2017-02-16

We present that the automation of the execution of computational tasks is at the heart of improving scientific productivity. Over the last years, scientific workflows have been established as an important abstraction that captures data processing and computation of large and complex scientific applications. By allowing scientists to model and express entire data processing steps and their dependencies, workflow management systems relieve scientists from the details of an application and manage its execution on a computational infrastructure. As the resource requirements of today’s computational and data science applications that process vast amounts of data keep increasing, there is a compellingmore » case for a new generation of advances in high-performance computing, commonly termed as extreme-scale computing, which will bring forth multiple challenges for the design of workflow applications and management systems. This paper presents a novel characterization of workflow management systems using features commonly associated with extreme-scale computing applications. We classify 15 popular workflow management systems in terms of workflow execution models, heterogeneous computing environments, and data access methods. Finally, the paper also surveys workflow applications and identifies gaps for future research on the road to extreme-scale workflows and management systems.« less

Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: insights from recording multiple ion currents in each cell.

PubMed

Monfredi, Oliver; Tsutsui, Kenta; Ziman, Bruce; Stern, Michael D; Lakatta, Edward G; Maltsev, Victor A

2018-03-01

Cardiac pacemaker cells, including cells of the sinoatrial node, are heterogeneous in size, morphology, and electrophysiological characteristics. The exact extent to which these cells differ electrophysiologically is unclear yet is critical to understanding their functioning. We examined major ionic currents in individual intercaval pacemaker cells (IPCs) sampled from the paracristal, intercaval region (including the sinoatrial node) that were spontaneously beating after enzymatic isolation from rabbit hearts. The beating rate was measured at baseline and after inhibition of the Ca 2+ pump with cyclopiazonic acid. Thereafter, in each cell, we consecutively measured the density of funny current ( I f ), delayed rectifier K + current ( I K ) (a surrogate of repolarization capacity), and L-type Ca 2+ current ( I Ca,L ) using whole cell patch clamp . The ionic current densities varied to a greater extent than previously appreciated, with some IPCs demonstrating very small or zero I f . The density of none of the currents was correlated with cell size, while I Ca,L and I f densities were related to baseline beating rates. I f density was correlated with I K density but not with that of I Ca,L . Inhibition of Ca 2+ cycling had a greater beating rate slowing effect in IPCs with lower I f densities. Our numerical model simulation indicated that 1) IPCs with small (or zero) I f or small I Ca,L can operate via a major contribution of Ca 2+ clock, 2) I f -Ca 2+ -clock interplay could be important for robust pacemaking function, and 3) coupled I f - I K function could regulate maximum diastolic potential. Thus, we have demonstrated marked electrophysiological heterogeneity of IPCs. This heterogeneity is manifested in basal beating rate and response to interference of Ca 2+ cycling, which is linked to I f . NEW & NOTEWORTHY In the present study, a hitherto unrecognized range of heterogeneity of ion currents in pacemaker cells from the intercaval region is demonstrated. Relationships between basal beating rate and L-type Ca 2+ current and funny current ( I f ) density are uncovered, along with a positive relationship between I f and delayed rectifier K + current. Links are shown between the response to Ca 2+ cycling blockade and I f density.

Utility functions and resource management in an oversubscribed heterogeneous computing environment

DOE PAGES

Khemka, Bhavesh; Friese, Ryan; Briceno, Luis Diego; ...

2014-09-26

We model an oversubscribed heterogeneous computing system where tasks arrive dynamically and a scheduler maps the tasks to machines for execution. The environment and workloads are based on those being investigated by the Extreme Scale Systems Center at Oak Ridge National Laboratory. Utility functions that are designed based on specifications from the system owner and users are used to create a metric for the performance of resource allocation heuristics. Each task has a time-varying utility (importance) that the enterprise will earn based on when the task successfully completes execution. We design multiple heuristics, which include a technique to drop lowmore » utility-earning tasks, to maximize the total utility that can be earned by completing tasks. The heuristics are evaluated using simulation experiments with two levels of oversubscription. The results show the benefit of having fast heuristics that account for the importance of a task and the heterogeneity of the environment when making allocation decisions in an oversubscribed environment. Furthermore, the ability to drop low utility-earning tasks allow the heuristics to tolerate the high oversubscription as well as earn significant utility.« less

Revisiting crash spatial heterogeneity: A Bayesian spatially varying coefficients approach.

PubMed

Xu, Pengpeng; Huang, Helai; Dong, Ni; Wong, S C

2017-01-01

This study was performed to investigate the spatially varying relationships between crash frequency and related risk factors. A Bayesian spatially varying coefficients model was elaborately introduced as a methodological alternative to simultaneously account for the unstructured and spatially structured heterogeneity of the regression coefficients in predicting crash frequencies. The proposed method was appealing in that the parameters were modeled via a conditional autoregressive prior distribution, which involved a single set of random effects and a spatial correlation parameter with extreme values corresponding to pure unstructured or pure spatially correlated random effects. A case study using a three-year crash dataset from the Hillsborough County, Florida, was conducted to illustrate the proposed model. Empirical analysis confirmed the presence of both unstructured and spatially correlated variations in the effects of contributory factors on severe crash occurrences. The findings also suggested that ignoring spatially structured heterogeneity may result in biased parameter estimates and incorrect inferences, while assuming the regression coefficients to be spatially clustered only is probably subject to the issue of over-smoothness. Copyright © 2016 Elsevier Ltd. All rights reserved.

Expanding the scale of molecular biophysics.

PubMed

Levine, Herbert

2016-10-07

Here, I argue that some of the secrets of complex biological function rely on assemblies of many heterogeneous proteins that together enable sophisticated sensing and actuating processes. Evolution seems to delight in making these structures and in continually elaborating upon their capabilities. Developing tools that can go beyond the few protein limit, both on the experimental frontier and from a theoretical, conceptual framework, should be an extremely high priority for the next generation of molecular biophysicists.

Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

DTIC Science & Technology

2013-03-14

SUPPLEMENTARY NOTES 14. ABSTRACT Autism is an extremely common and heterogeneous neurodevelopmental disorder. While genetic factors are known to play...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

Demonstration/Validation of Incremental Sampling at Two Diverse Military Ranges and Development of an Incremental Sampling Tool

DTIC Science & Technology

2010-06-01

Sampling (MIS)? • Technique of combining many increments of soil from a number of points within exposure area • Developed by Enviro Stat (Trademarked...Demonstrating a reliable soil sampling strategy to accurately characterize contaminant concentrations in spatially extreme and heterogeneous...into a set of decision (exposure) units • One or several discrete or small- scale composite soil samples collected to represent each decision unit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valous, Nektarios A.; Lahrmann, Bernd; Halama, Niels

Purpose: The interactions of neoplastic cells with each other and the microenvironment are complex. To understand intratumoral heterogeneity, subtle differences should be quantified. Main factors contributing to heterogeneity include the gradient ischemic level within neoplasms, action of microenvironment, mechanisms of intercellular transfer of genetic information, and differential mechanisms of modifications of genetic material/proteins. This may reflect on the expression of biomarkers in the context of prognosis/stratification. Hence, a rigorous approach for assessing the spatial intratumoral heterogeneity of histological biomarker expression with accuracy and reproducibility is required, since patterns in immunohistochemical images can be challenging to identify and describe. Methods: Amore » quantitative method that is useful for characterizing complex irregular structures is lacunarity; it is a multiscale technique that exhaustively samples the image, while the decay of its index as a function of window size follows characteristic patterns for different spatial arrangements. In histological images, lacunarity provides a useful measure for the spatial organization of a biomarker when a sampling scheme is employed and relevant features are computed. The proposed approach quantifies the segmented proliferative cells and not the textural content of the histological slide, thus providing a more realistic measure of heterogeneity within the sample space of the tumor region. The aim is to investigate in whole sections of primary pancreatic neuroendocrine neoplasms (pNENs), using whole-slide imaging and image analysis, the spatial intratumoral heterogeneity of Ki-67 immunostains. Unsupervised learning is employed to verify that the approach can partition the tissue sections according to distributional heterogeneity. Results: The architectural complexity of histological images has shown that single measurements are often insufficient. Inhomogeneity of distribution depends not only on percentage content of proliferation phase but also on how the phase fills the space. Lacunarity curves demonstrate variations in the sampled image sections. Since the spatial distribution of proliferation in each case is different, the width of the curves changes too. Image sections that have smaller numerical variations in the computed features correspond to neoplasms with spatially homogeneous proliferation, while larger variations correspond to cases where proliferation shows various degrees of clumping. Grade 1 (uniform/nonuniform: 74%/26%) and grade 3 (uniform: 100%) pNENs demonstrate a more homogeneous proliferation with grade 1 neoplasms being more variant, while grade 2 tumor regions render a more diverse landscape (50%/50%). Hence, some cases show an increased degree of spatial heterogeneity comparing to others with similar grade. Whether this is a sign of different tumor biology and an association with a more benign/malignant clinical course needs to be investigated further. The extent and range of spatial heterogeneity has the potential to be evaluated as a prognostic marker. Conclusions: The association with tumor grade as well as the rationale that the methodology reflects true tumor architecture supports the technical soundness of the method. This reflects a general approach which is relevant to other solid tumors and biomarkers. Drawing upon the merits of computational biomedicine, the approach uncovers salient features for use in future studies of clinical relevance.« less

Noninvasive biosensor for hypoglycemia

NASA Astrophysics Data System (ADS)

Varadan, Vijay K.; Whitchurch, Ashwin K.; Sarukesi, Karunakaran

2003-01-01

Hypoglycemia-abnormal decrease in blood sugar- is a major obstacle in the management of diabetes and prevention of long-term complications, and it may impose serious effects on the brain, including impairment of memory and other cognitive functions. This is especially a concern in early childhood years when the nervous system is still developing. Hypoglycemic unawareness (in which the body"s normal ability to signal low blood sugar doesn"t work and an oncoming low blood sugar episode proceeds undetected) is a particularly frightening problem for many people with diabetes. Researchers have now uncovered evidence that repeated bouts of insulin-induced hypoglycemia can harm the brain over time, causing confusion, abnormal behavior, loss of consciousness, and seizures. Extreme cases have resulted in coma and death. In this paper, a non-invasive biosensor in a wrist watch along with a wireless data downloading system is proposed.

A Review on Experimental Measurements for Understanding Efficiency Droop in InGaN-Based Light-Emitting Diodes

PubMed Central

Jin, Jie; Mi, Chenziyi; Hao, Zhibiao; Luo, Yi; Sun, Changzheng; Han, Yanjun; Xiong, Bing; Wang, Jian; Li, Hongtao

2017-01-01

Efficiency droop in GaN-based light emitting diodes (LEDs) under high injection current density perplexes the development of high-power solid-state lighting. Although the relevant study has lasted for about 10 years, its mechanism is still not thoroughly clear, and consequently its solution is also unsatisfactory up to now. Some emerging applications, e.g., high-speed visible light communication, requiring LED working under extremely high current density, makes the influence of efficiency droop become more serious. This paper reviews the experimental measurements on LED to explain the origins of droop in recent years, especially some new results reported after 2013. Particularly, the carrier lifetime of LED is analyzed intensively and its effects on LED droop behaviors are uncovered. Finally, possible solutions to overcome LED droop are discussed. PMID:29072611

Radiocarbon reservoir between charred seeds and fish bone in Neolithic sites, northeastern Qinghai-Tibetan Plateau

NASA Astrophysics Data System (ADS)

Zhou, A.; Dong, G.; Ren, L.

2017-12-01

Many efforts have been done to understand the reservoir effect of Qinghai Lake, yet no agreement has been reached. Five archaeological sites, located around the junction between the estuary of Rivers and Qinghai Lake, are the earliest Neolithic Age sites in the Qinghai- Tibetan Plateau (QTP), which is critical for understanding patterns of prehistoric human inhabitation in the high plateau extreme environments. This study compares radiocarbon dates of fish bones and terrestrial plant remains uncovered from the same archaeological strata to see whether there was reservoir effect reference to reliable data. Results demonstrate that there were reservoir effects ranging from 300 to 600 years back to 3600 years ago, nevertheless, no reservoir was observed of the modern fish. Besides, stable isotopic analysis illustrated that modern fish consumed similar food to those of millennias ago.

Inferring phenomenological models of Markov processes from data

NASA Astrophysics Data System (ADS)

Rivera, Catalina; Nemenman, Ilya

Microscopically accurate modeling of stochastic dynamics of biochemical networks is hard due to the extremely high dimensionality of the state space of such networks. Here we propose an algorithm for inference of phenomenological, coarse-grained models of Markov processes describing the network dynamics directly from data, without the intermediate step of microscopically accurate modeling. The approach relies on the linear nature of the Chemical Master Equation and uses Bayesian Model Selection for identification of parsimonious models that fit the data. When applied to synthetic data from the Kinetic Proofreading process (KPR), a common mechanism used by cells for increasing specificity of molecular assembly, the algorithm successfully uncovers the known coarse-grained description of the process. This phenomenological description has been notice previously, but this time it is derived in an automated manner by the algorithm. James S. McDonnell Foundation Grant No. 220020321.

A study of the viability of exploiting memory content similarity to improve resilience to memory errors

DOE PAGES

Levy, Scott; Ferreira, Kurt B.; Bridges, Patrick G.; ...

2014-12-09

Building the next-generation of extreme-scale distributed systems will require overcoming several challenges related to system resilience. As the number of processors in these systems grow, the failure rate increases proportionally. One of the most common sources of failure in large-scale systems is memory. In this paper, we propose a novel runtime for transparently exploiting memory content similarity to improve system resilience by reducing the rate at which memory errors lead to node failure. We evaluate the viability of this approach by examining memory snapshots collected from eight high-performance computing (HPC) applications and two important HPC operating systems. Based on themore » characteristics of the similarity uncovered, we conclude that our proposed approach shows promise for addressing system resilience in large-scale systems.« less

KSC-2012-3804

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians offload and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3800

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncrate, offload and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3788

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians offload and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3811

NASA Image and Video Library

2012-07-13

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncover and inspect the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3787

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncrate and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3795

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncrate and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3789

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians offload, inspect and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3805

NASA Image and Video Library

2012-07-13

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians inspect and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3799

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians offload, inspect and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3796

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncrate and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3810

NASA Image and Video Library

2012-07-13

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft is being uncovered for inspection. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3798

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians offload and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3786

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncrate and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3797

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncrate, inspect and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3802

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians uncrate, inspect and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3791

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians offload, inspect and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3801

NASA Image and Video Library

2012-07-12

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians offload, inspect and prepare to uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

New online ecology of adversarial aggregates: ISIS and beyond.

PubMed

Johnson, N F; Zheng, M; Vorobyeva, Y; Gabriel, A; Qi, H; Velasquez, N; Manrique, P; Johnson, D; Restrepo, E; Song, C; Wuchty, S

2016-06-17

Support for an extremist entity such as Islamic State (ISIS) somehow manages to survive globally online despite considerable external pressure and may ultimately inspire acts by individuals having no history of extremism, membership in a terrorist faction, or direct links to leadership. Examining longitudinal records of online activity, we uncovered an ecology evolving on a daily time scale that drives online support, and we provide a mathematical theory that describes it. The ecology features self-organized aggregates (ad hoc groups formed via linkage to a Facebook page or analog) that proliferate preceding the onset of recent real-world campaigns and adopt novel adaptive mechanisms to enhance their survival. One of the predictions is that development of large, potentially potent pro-ISIS aggregates can be thwarted by targeting smaller ones. Copyright © 2016, American Association for the Advancement of Science.

Five-year forward view: lessons from emergency care at the extremes of age.

PubMed

Minhas, J S; Minhas, D; Coats, T; Banerjee, J; Roland, D

2018-03-01

Objective The progressive rise in demand on NHS emergency care resources is partly attributable to increases in attendances of children and older people. A quality gap exists in the care provision for the old and the young. The Five Year Forward View suggested new models of care but that the "answer is not one-size-fits-all". This article discusses the urgent need for person-centred outcome measures to bridge the gap that exists between demand and provision. Design This review is based on evidence gathered from literature searching across several platforms using a variety of search terms to account for the obvious heterogeneity, drawing on key 'think-tank' evidence. Settings Qualitative and quantitative studies examining approaches to caring for individuals at the extremes of age. Participants Individuals at the extremes of age (infants and older people). Main Outcome Measures Understanding similarities and disparities in the care of individuals at the extremes of age in an emergency and non-emergency context. Results There exists several similarities and disparities in the care of individuals at the extremes of age. The increasing burden of health disease on the economy must acknowledge the challenges that exist in managing patients in emergency settings at the extremes of age and build systems to acknowledge the traits these individuals exhibit. Conclusion Commissioners of services must optimise the models of care delivery by appreciating the similarities and differences between care requirements in these two large groups seeking emergency care.

Extracellular Ca2(+)-dependent inducible alkaline phosphatase from extremely halophilic archaebacterium Haloarcula marismortui.

PubMed Central

Goldman, S; Hecht, K; Eisenberg, H; Mevarech, M

1990-01-01

When starved of inorganic phosphate, the extremely halophilic archaebacterium Haloarcula marismortui produces the enzyme alkaline phosphatase and secretes it to the medium. This inducible extracellular enzyme is a glycoprotein whose subunit molecular mass is 160 kDa, as estimated by sodium dodecyl sulfate-gel electrophoresis. The native form of the enzyme is heterogeneous and composed of multiple oligomeric forms. The enzymatic activity of the halophilic alkaline phosphatase is maximal at pH 8.5, and the enzyme is inhibited by phosphate. Unlike most alkaline phosphatases, the halobacterial enzyme requires Ca2+ and not Zn2+ ions for its activity. Both calcium ions (in the millimolar range) and NaCl (in the molar range) are required for the stability of the enzyme. Images PMID:2123861

Spatial heterogeneity of water quality in a highly degraded tropical freshwater ecosystem.

PubMed

Zambrano, Luis; Contreras, Victoria; Mazari-Hiriart, Marisa; Zarco-Arista, Alba E

2009-02-01

Awareness of environmental heterogeneity in ecosystems is critical for management and conservation. We used the Xochimilco freshwater system to describe the relationship between heterogeneity and human activities. This tropical aquatic ecosystem south of Mexico City is comprised of a network of interconnected canals and lakes that are influenced by agricultural and urban activities. Environmental heterogeneity was characterized by spatially extensive surveys within four regions of Xochimilco during rainy and dry seasons over 2 years. These surveys revealed a heterogeneous system that was shallow (1.1 m, SD=0.4 ), warm (17 degrees C, SD=2.9), well oxygenated (5.0 mg l(-1), SD=3), turbid (45.7 NTU SD = 26.96), and extremely nutrient-rich (NO(3)-N=15.9 mg l(-1), SD=13.7; NH(4)-N=2.88 mg l(-1), SD=4.24; and PO(4)-P=8.3 mg l(-1), SD=2.4). Most of the variables were not significantly different between years, but did differ between seasons, suggesting a dynamic system within a span of a year but with a high resilience over longer periods of time. Maps were produced using interpolations to describe distributions of all variables. There was no correlation between individual variables and land use. Consequently, we searched for relationships using all variables together by generating a combined water quality index. Significant differences in the index were apparent among the four regions. Index values also differed within individual region and individual water bodies (e.g., within canals), indicating that Xochimilco has high local heterogeneity. Using this index on a map helped to relate water quality to human activities and provides a simple and clear tool for managers and policymakers.

Spatial Heterogeneity of Water Quality in a Highly Degraded Tropical Freshwater Ecosystem

NASA Astrophysics Data System (ADS)

Zambrano, Luis; Contreras, Victoria; Mazari-Hiriart, Marisa; Zarco-Arista, Alba E.

2009-02-01

Awareness of environmental heterogeneity in ecosystems is critical for management and conservation. We used the Xochimilco freshwater system to describe the relationship between heterogeneity and human activities. This tropical aquatic ecosystem south of Mexico City is comprised of a network of interconnected canals and lakes that are influenced by agricultural and urban activities. Environmental heterogeneity was characterized by spatially extensive surveys within four regions of Xochimilco during rainy and dry seasons over 2 years. These surveys revealed a heterogeneous system that was shallow (1.1 m, SD = 0.4 ), warm (17°C, SD = 2.9), well oxygenated (5.0 mg l-1, SD = 3), turbid (45.7 NTU SD = 26.96), and extremely nutrient-rich (NO3-N = 15.9 mg l-1, SD=13.7; NH4-N = 2.88 mg l-1, SD = 4.24; and PO4-P = 8.3 mg l-1, SD = 2.4). Most of the variables were not significantly different between years, but did differ between seasons, suggesting a dynamic system within a span of a year but with a high resilience over longer periods of time. Maps were produced using interpolations to describe distributions of all variables. There was no correlation between individual variables and land use. Consequently, we searched for relationships using all variables together by generating a combined water quality index. Significant differences in the index were apparent among the four regions. Index values also differed within individual region and individual water bodies (e.g., within canals), indicating that Xochimilco has high local heterogeneity. Using this index on a map helped to relate water quality to human activities and provides a simple and clear tool for managers and policymakers.

Spatial intratumoral heterogeneity of proliferation in immunohistochemical images of solid tumors.

PubMed

Valous, Nektarios A; Lahrmann, Bernd; Halama, Niels; Bergmann, Frank; Jäger, Dirk; Grabe, Niels

2016-06-01

The interactions of neoplastic cells with each other and the microenvironment are complex. To understand intratumoral heterogeneity, subtle differences should be quantified. Main factors contributing to heterogeneity include the gradient ischemic level within neoplasms, action of microenvironment, mechanisms of intercellular transfer of genetic information, and differential mechanisms of modifications of genetic material/proteins. This may reflect on the expression of biomarkers in the context of prognosis/stratification. Hence, a rigorous approach for assessing the spatial intratumoral heterogeneity of histological biomarker expression with accuracy and reproducibility is required, since patterns in immunohistochemical images can be challenging to identify and describe. A quantitative method that is useful for characterizing complex irregular structures is lacunarity; it is a multiscale technique that exhaustively samples the image, while the decay of its index as a function of window size follows characteristic patterns for different spatial arrangements. In histological images, lacunarity provides a useful measure for the spatial organization of a biomarker when a sampling scheme is employed and relevant features are computed. The proposed approach quantifies the segmented proliferative cells and not the textural content of the histological slide, thus providing a more realistic measure of heterogeneity within the sample space of the tumor region. The aim is to investigate in whole sections of primary pancreatic neuroendocrine neoplasms (pNENs), using whole-slide imaging and image analysis, the spatial intratumoral heterogeneity of Ki-67 immunostains. Unsupervised learning is employed to verify that the approach can partition the tissue sections according to distributional heterogeneity. The architectural complexity of histological images has shown that single measurements are often insufficient. Inhomogeneity of distribution depends not only on percentage content of proliferation phase but also on how the phase fills the space. Lacunarity curves demonstrate variations in the sampled image sections. Since the spatial distribution of proliferation in each case is different, the width of the curves changes too. Image sections that have smaller numerical variations in the computed features correspond to neoplasms with spatially homogeneous proliferation, while larger variations correspond to cases where proliferation shows various degrees of clumping. Grade 1 (uniform/nonuniform: 74%/26%) and grade 3 (uniform: 100%) pNENs demonstrate a more homogeneous proliferation with grade 1 neoplasms being more variant, while grade 2 tumor regions render a more diverse landscape (50%/50%). Hence, some cases show an increased degree of spatial heterogeneity comparing to others with similar grade. Whether this is a sign of different tumor biology and an association with a more benign/malignant clinical course needs to be investigated further. The extent and range of spatial heterogeneity has the potential to be evaluated as a prognostic marker. The association with tumor grade as well as the rationale that the methodology reflects true tumor architecture supports the technical soundness of the method. This reflects a general approach which is relevant to other solid tumors and biomarkers. Drawing upon the merits of computational biomedicine, the approach uncovers salient features for use in future studies of clinical relevance.

A comparison of solute-transport solution techniques based on inverse modelling results

USGS Publications Warehouse

Mehl, S.; Hill, M.C.

2000-01-01

Five common numerical techniques (finite difference, predictor-corrector, total-variation-diminishing, method-of-characteristics, and modified-method-of-characteristics) were tested using simulations of a controlled conservative tracer-test experiment through a heterogeneous, two-dimensional sand tank. The experimental facility was constructed using randomly distributed homogeneous blocks of five sand types. This experimental model provides an outstanding opportunity to compare the solution techniques because of the heterogeneous hydraulic conductivity distribution of known structure, and the availability of detailed measurements with which to compare simulated concentrations. The present work uses this opportunity to investigate how three common types of results-simulated breakthrough curves, sensitivity analysis, and calibrated parameter values-change in this heterogeneous situation, given the different methods of simulating solute transport. The results show that simulated peak concentrations, even at very fine grid spacings, varied because of different amounts of numerical dispersion. Sensitivity analysis results were robust in that they were independent of the solution technique. They revealed extreme correlation between hydraulic conductivity and porosity, and that the breakthrough curve data did not provide enough information about the dispersivities to estimate individual values for the five sands. However, estimated hydraulic conductivity values are significantly influenced by both the large possible variations in model dispersion and the amount of numerical dispersion present in the solution technique.Five common numerical techniques (finite difference, predictor-corrector, total-variation-diminishing, method-of-characteristics, and modified-method-of-characteristics) were tested using simulations of a controlled conservative tracer-test experiment through a heterogeneous, two-dimensional sand tank. The experimental facility was constructed using randomly distributed homogeneous blocks of five sand types. This experimental model provides an outstanding opportunity to compare the solution techniques because of the heterogeneous hydraulic conductivity distribution of known structure, and the availability of detailed measurements with which to compare simulated concentrations. The present work uses this opportunity to investigate how three common types of results - simulated breakthrough curves, sensitivity analysis, and calibrated parameter values - change in this heterogeneous situation, given the different methods of simulating solute transport. The results show that simulated peak concentrations, even at very fine grid spacings, varied because of different amounts of numerical dispersion. Sensitivity analysis results were robust in that they were independent of the solution technique. They revealed extreme correlation between hydraulic conductivity and porosity, and that the breakthrough curve data did not provide enough information about the dispersivities to estimate individual values for the five sands. However, estimated hydraulic conductivity values are significantly influenced by both the large possible variations in model dispersion and the amount of numerical dispersion present in the solution technique.

78 FR 41784 - Uncovered Innerspring Units From the People's Republic of China: Affirmative Preliminary...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-11

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-928] Uncovered Innerspring Units... Commerce. Preliminary Determination The Department has preliminarily determined that uncovered innerspring... Commerce, 14th Street and Constitution Avenue NW., Washington, DC 20230; telephone: (202) [[Page 41785...

Genetic heterogeneity in wild isolates of cellular slime mold social groups.

PubMed

Sathe, Santosh; Kaushik, Sonia; Lalremruata, Albert; Aggarwal, Ramesh K; Cavender, James C; Nanjundiah, Vidyanand

2010-07-01

This study addresses the issues of spatial distribution, dispersal, and genetic heterogeneity in social groups of the cellular slime molds (CSMs). The CSMs are soil amoebae with an unusual life cycle that consists of alternating solitary and social phases. Because the social phase involves division of labor with what appears to be an extreme form of "altruism", the CSMs raise interesting evolutionary questions regarding the origin and maintenance of sociality. Knowledge of the genetic structure of social groups in the wild is necessary for answering these questions. We confirm that CSMs are widespread in undisturbed forest soil from South India. They are dispersed over long distances via the dung of a variety of large mammals. Consistent with this mode of dispersal, most social groups in the two species examined for detailed study, Dictyostelium giganteum and Dictyostelium purpureum, are multi-clonal.

WRF-Hydro Simulated Spatiotemporal Characteristics of Streamflow Extremes over the CONUS during 1993-2016 and Possible Connections with Climate Variability

NASA Astrophysics Data System (ADS)

Dugger, A. L.; Zhang, Y.; Gochis, D.; Yu, W.; McCreight, J. L.; Karsten, L.; Rafieeinasab, A.; Sampson, K. M.; Salas, F.; Read, L.; Pan, L.; Yates, D. N.; Cosgrove, B.; Clark, E. P.

2017-12-01

Streamflow extremes (lows and peaks) tend to have disproportionately higher impacts on the human and natural systems compared to mean streamflow. Examining and understanding the spatiotemporal distributions of streamflow extremes is of significant interests to both the research community and the water resources management. In this work, the output from the 24-year (1993 through 2016) retrospective runs of the National Water Model (NWM) version of WRF-Hydro will be analyzed for streamflow extremes over the CONUS domain. The CONUS domain was configured at 1-km resolution for land surface grid and 250-m resolution for terrain routing. The WRF-Hydro runs were forced by the regridded and downscaled NLDAS2 data. The analyses focus on daily mean streamflow values over the full water year and within the summer and winter seasons. Connections between NWM streamflow and other hydrologic variables (e.g. snowpack, soil moisture/saturation and ET) with variations in large-scale climate phenomena, e.g., El Niño - Southern Oscillation (ENSO), North Atlantic Oscillation (NAO), and North American monsoon are examined. The CONUS domain has a diverse environment and is characterized by complex terrain, heterogeneous land surfaces and ecosystems, and numerous hydrological basins. The potential dependence of streamflow extremes on regional terrain character, climatic conditions, and ecologic zones will also be investigated.

Conformable covered versus uncovered self-expandable metallic stents for palliation of malignant gastroduodenal obstruction: a randomized prospective study.

PubMed

Lim, Sun Gyo; Kim, Jin Hong; Lee, Kee Myung; Shin, Sung Jae; Kim, Chan Gyoo; Kim, Kyung Ho; Kim, Ho Gak; Yang, Chang Heon

2014-07-01

A conformable self-expandable metallic stent was developed to overcome the limitation of previous self-expandable metallic stents. The aim of this study was to evaluate outcomes after placement of conformable covered and uncovered self-expandable metallic stents for palliation of malignant gastroduodenal obstruction. A single-blind, randomized, parallel-group, prospective study were conducted in 4 medical centres between March 2009 and July 2012. 134 patients with unresectable malignant gastroduodenal obstruction were assigned to a covered double-layered (n=66) or uncovered unfixed-cell braided (n=68) stent placement group. Primary analysis was performed to compare re-intervention rates between two groups. 120 patients were analysed (59 in the covered group and 61 in the uncovered group). Overall rates of re-intervention were not significantly different between the two groups: 13/59 (22.0%) in the covered group vs. 13/61 (21.3%) in the uncovered group, p=0.999. Stent migration was more frequent in the covered group than in the uncovered group (p=0.003). The tumour ingrowth rate was higher in the uncovered group than in the covered group (p=0.016). The rates of re-intervention did not significantly differ between the two stents. Conformable covered double-layered and uncovered unfixed-cell braided stents were associated with different patterns of stent malfunction. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

The Rb problem in massive AGB stars.

NASA Astrophysics Data System (ADS)

Pérez-Mesa, V.; García-Hernández, D. A.; Zamora, O.; Plez, B.; Manchado, A.; Karakas, A. I.; Lugaro, M.

2017-03-01

The asymptotic giant branch (AGB) is formed by low- and intermediate-mass stars (0.8 M_{⊙} < M < 8 M_{⊙}) in their last nuclear-burning phase, when they develop thermal pulses (TP) and suffer extreme mass loss. AGB stars are the main contributor to the enrichment of the interstellar medium (ISM) and thus to the chemical evolution of galaxies. In particular, the more massive AGB stars (M > 4 M_{⊙}) are expected to produce light (e.g., Li, N) and heavy neutron-rich s-process elements (such as Rb, Zr, Ba, Y, etc.), which are not formed in lower mass AGB stars and Supernova explosions. Classical chemical analyses using hydrostatic atmospheres revealed strong Rb overabundances and high [Rb/Zr] ratios in massive AGB stars of our Galaxy and the Magellanic Clouds (MC), confirming for the first time that the ^{22}Ne neutron source dominates the production of s-process elements in these stars. The extremely high Rb abundances and [Rb/Zr] ratios observed in the most massive stars (specially in the low-metallicity MC stars) uncovered a Rb problem; such extreme Rb and [Rb/Zr] values are not predicted by the s-process AGB models, suggesting fundamental problems in our present understanding of their atmospheres. We present more realistic dynamical model atmospheres that consider a gaseous circumstellar envelope with a radial wind and we re-derive the Rb (and Zr) abundances in massive Galactic AGB stars. The new Rb abundances and [Rb/Zr] ratios derived with these dynamical models significantly resolve the problem of the mismatch between the observations and the theoretical predictions of the more massive AGB stars.

Low density of neutral hydrogen and helium in the local interstellar medium: Extreme Ultraviolet Explorer photometry of the Lyman continuum of the hot white dwarfs MCT 0501-2858, MCT 0455-2812, HZ 43, and GD 153

NASA Technical Reports Server (NTRS)

Vennes, Stephane; Dupuis, Jean; Bowyer, Stuart; Fontaine, Gilles; Wiercigroch, Alexandria; Jelinsky, Patrick; Wesemael, Francois; Malina, Roger

1994-01-01

The first comprehensive sky survey of the extreme ultraviolet (EUV) spectral range performed by the Extreme Ultraviolet Explorer (EUVE) has uncovered a handful of very bright sources at wavelengths longer than the He I 504 A photoionization edge. Among these objects are four white dwarfs with exceptionally low interstellar medium (ISM) column densities along the line of sight. Analysis of EUV photometry of the He-rich DO white dwarf MCT 0501-2858 and the H-rich DA white dwarf MCT 0455-2812 along one line of sight and of the DA white dwarfs HZ 43 and GD 153 near the north Galactic pole indicates that the overall minimum column density of the neutral material centered on the Sun is N(H I) = 0.5-1.0 x 10(exp 18)/sq cm. In the case of MCT 0501-2858, EUV photometric measurements provide a clear constraint to the effective temperature (60,000-70,000 K). Given these neutral hydrogen columns, the actual contribution to the density of neutral species from the immediate solar environment (the 'local fluff') would only cover a distance of approximately equals 2-3 pc (assuming an average density n(H I) = 0.1/cu cm) leaving these lines of sight almost entirely within the hot phase of the ISM. A preliminary examination of the complete EUVE long-wavelength survey indicates that these lines of sight are exceptional and set a minimum column density in the solar environment.

Adaptation to flood risk: Results of international paired flood event studies

NASA Astrophysics Data System (ADS)

Kreibich, Heidi; Di Baldassarre, Giuliano; Vorogushyn, Sergiy; Aerts, Jeroen C. J. H.; Apel, Heiko; Aronica, Giuseppe T.; Arnbjerg-Nielsen, Karsten; Bouwer, Laurens M.; Bubeck, Philip; Caloiero, Tommaso; Chinh, Do T.; Cortès, Maria; Gain, Animesh K.; Giampá, Vincenzo; Kuhlicke, Christian; Kundzewicz, Zbigniew W.; Llasat, Maria Carmen; Mârd, Johanna; Matczak, Piotr; Mazzoleni, Maurizio; Molinari, Daniela; Dung, Nguyen V.; Petrucci, Olga; Schröter, Kai; Slager, Kymo; Thieken, Annegret H.; Ward, Philip J.; Merz, Bruno

2017-10-01

As flood impacts are increasing in large parts of the world, understanding the primary drivers of changes in risk is essential for effective adaptation. To gain more knowledge on the basis of empirical case studies, we analyze eight paired floods, that is, consecutive flood events that occurred in the same region, with the second flood causing significantly lower damage. These success stories of risk reduction were selected across different socioeconomic and hydro-climatic contexts. The potential of societies to adapt is uncovered by describing triggered societal changes, as well as formal measures and spontaneous processes that reduced flood risk. This novel approach has the potential to build the basis for an international data collection and analysis effort to better understand and attribute changes in risk due to hydrological extremes in the framework of the IAHSs Panta Rhei initiative. Across all case studies, we find that lower damage caused by the second event was mainly due to significant reductions in vulnerability, for example, via raised risk awareness, preparedness, and improvements of organizational emergency management. Thus, vulnerability reduction plays an essential role for successful adaptation. Our work shows that there is a high potential to adapt, but there remains the challenge to stimulate measures that reduce vulnerability and risk in periods in which extreme events do not occur.

Uncovering of melanin fluorescence in human skin tissue

NASA Astrophysics Data System (ADS)

Scholz, Matthias; Stankovic, Goran; Seewald, Gunter; Leupold, Dieter

2007-07-01

Due to its extremely low fluorescence quantum yield, in the conventionally (one-photon) excited autofluorescence of skin tissue, melanin fluorescence is masked by several other endogenous and possibly also exogenous fluorophores (e.g. NADH, FAD, Porphyrins). A first step to enhance the melanin contribution had been realized by two-photon fs-pulse excitation in the red/near IR, based on the fact that melanin can be excited by stepwise two-photon absorption, whereas all other fluorophores in this spectral region allow only simultaneous two-photon excitation. Now, the next and decisive step has been realized: Using an extremely sensitive detection system, for the first time twophoton fluorescence of skin tissue excited with pulses in the ns-range could be measured. The motivation for this step was based on the fact that the population density of the fluorescent level resulting from a stepwise excitation has a different dependence of the pulse duration than that from a simultaneous excitation (Δt2 vs. Δt). Due to this strong discrimination between the fluorophores, practically pure melanin fluorescence can be obtained. Examples for in-vivo, ex-vivo as well as paraffin embedded skin tissue will be shown. The content of information with respect to early diagnosis of skin deseases will be discussed.

Comparative metagenomic and metatranscriptomic analyses of microbial communities in acid mine drainage.

PubMed

Chen, Lin-xing; Hu, Min; Huang, Li-nan; Hua, Zheng-shuang; Kuang, Jia-liang; Li, Sheng-jin; Shu, Wen-sheng

2015-07-01

The microbial communities in acid mine drainage have been extensively studied to reveal their roles in acid generation and adaption to this environment. Lacking, however, are integrated community- and organism-wide comparative gene transcriptional analyses that could reveal the response and adaptation mechanisms of these extraordinary microorganisms to different environmental conditions. In this study, comparative metagenomics and metatranscriptomics were performed on microbial assemblages collected from four geochemically distinct acid mine drainage (AMD) sites. Taxonomic analysis uncovered unexpectedly high microbial biodiversity of these extremely acidophilic communities, and the abundant taxa of Acidithiobacillus, Leptospirillum and Acidiphilium exhibited high transcriptional activities. Community-wide comparative analyses clearly showed that the AMD microorganisms adapted to the different environmental conditions via regulating the expression of genes involved in multiple in situ functional activities, including low-pH adaptation, carbon, nitrogen and phosphate assimilation, energy generation, environmental stress resistance, and other functions. Organism-wide comparative analyses of the active taxa revealed environment-dependent gene transcriptional profiles, especially the distinct strategies used by Acidithiobacillus ferrivorans and Leptospirillum ferrodiazotrophum in nutrients assimilation and energy generation for survival under different conditions. Overall, these findings demonstrate that the gene transcriptional profiles of AMD microorganisms are closely related to the site physiochemical characteristics, providing clues into the microbial response and adaptation mechanisms in the oligotrophic, extremely acidic environments.

Magnetic field generation, Weibel-mediated collisionless shocks, and magnetic reconnection in colliding laser-produced plasmas

NASA Astrophysics Data System (ADS)

Fox, W.; Bhattacharjee, A.; Fiksel, G.

2016-10-01

Colliding plasmas are ubiquitous in astrophysical environments and allow conversion of kinetic energy into heat and, most importantly, the acceleration of particles to extremely high energies to form the cosmic ray spectrum. In collisionless astrophysical plasmas, kinetic plasma processes govern the interaction and particle acceleration processes, including shock formation, self-generation of magnetic fields by kinetic plasma instabilities, and magnetic field compression and reconnection. How each of these contribute to the observed spectra of cosmic rays is not fully understood, in particular both shock acceleration processes and magnetic reconnection have been proposed. We will review recent results of laboratory astrophysics experiments conducted at high-power, inertial-fusion-class laser facilities, which have uncovered significant results relevant to these processes. Recent experiments have now observed the long-sought Weibel instability between two interpenetrating high temperature plasma plumes, which has been proposed to generate the magnetic field necessary for shock formation in unmagnetized regimes. Secondly, magnetic reconnection has been studied in systems of colliding plasmas using either self-generated magnetic fields or externally applied magnetic fields, and show extremely fast reconnection rates, indicating fast destruction of magnetic energy and further possibilities to accelerate particles. Finally, we highlight kinetic plasma simulations, which have proven to be essential tools in the design and interpretation of these experiments.

Materials and Coatings for Extreme Performances: Investigations, Applications, Ecologically Safe Technologies for Their Production and Utilization

DTIC Science & Technology

2004-11-16

1) E170 CORROSION RESICTANCE OF Ti AND ITS ALLOYS IN SEA WATER Vyazovikina N.V., Kus’menko H.H., Kulak L.D., Vyazovikin I.V.(1) E45 TECHNOLOGICAL...INFLUENCE OF CORROSION IN SEA WATER ENVIRONMENT ON PHYSICO – MECHANICAL PROPERTIES OF GREEN BODIES FABRICATED FROM A COPPER BASED HETEROGENEOUS MATERIAL...high chemical stability (tolerance towards gasoline, sea water, acids and alkali), reduced flammability, low adhesion to dirtying substances. In

Rapid Deployment of Optimal Control for Building HVAC Systems using Innovative Software Tools and a Hybrid Heuristic/Model Based Control Approach

DTIC Science & Technology

2017-03-21

Energy and Water Projects March 21, 2017 REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this collection of...included reduced system energy use and cost as well as improved performance driven by autonomous commissioning and optimized system control. In the end...improve system performance and reduce energy use and cost. However, implementing these solutions into the extremely heterogeneous and often

Mortality Measurement at Advanced Ages: A Study of the Social Security Administration Death Master File

PubMed Central

Gavrilov, Leonid A.; Gavrilova, Natalia S.

2011-01-01

Accurate estimates of mortality at advanced ages are essential to improving forecasts of mortality and the population size of the oldest old age group. However, estimation of hazard rates at extremely old ages poses serious challenges to researchers: (1) The observed mortality deceleration may be at least partially an artifact of mixing different birth cohorts with different mortality (heterogeneity effect); (2) standard assumptions of hazard rate estimates may be invalid when risk of death is extremely high at old ages and (3) ages of very old people may be exaggerated. One way of obtaining estimates of mortality at extreme ages is to pool together international records of persons surviving to extreme ages with subsequent efforts of strict age validation. This approach helps researchers to resolve the third of the above-mentioned problems but does not resolve the first two problems because of inevitable data heterogeneity when data for people belonging to different birth cohorts and countries are pooled together. In this paper we propose an alternative approach, which gives an opportunity to resolve the first two problems by compiling data for more homogeneous single-year birth cohorts with hazard rates measured at narrow (monthly) age intervals. Possible ways of resolving the third problem of hazard rate estimation are elaborated. This approach is based on data from the Social Security Administration Death Master File (DMF). Some birth cohorts covered by DMF could be studied by the method of extinct generations. Availability of month of birth and month of death information provides a unique opportunity to obtain hazard rate estimates for every month of age. Study of several single-year extinct birth cohorts shows that mortality trajectory at advanced ages follows the Gompertz law up to the ages 102–105 years without a noticeable deceleration. Earlier reports of mortality deceleration (deviation of mortality from the Gompertz law) at ages below 100 appear to be artifacts of mixing together several birth cohorts with different mortality levels and using cross-sectional instead of cohort data. Age exaggeration and crude assumptions applied to mortality estimates at advanced ages may also contribute to mortality underestimation at very advanced ages. PMID:22308064

Hierarchical Bayesian modeling of heterogeneous variances in average daily weight gain of commercial feedlot cattle.

PubMed

Cernicchiaro, N; Renter, D G; Xiang, S; White, B J; Bello, N M

2013-06-01

Variability in ADG of feedlot cattle can affect profits, thus making overall returns more unstable. Hence, knowledge of the factors that contribute to heterogeneity of variances in animal performance can help feedlot managers evaluate risks and minimize profit volatility when making managerial and economic decisions in commercial feedlots. The objectives of the present study were to evaluate heteroskedasticity, defined as heterogeneity of variances, in ADG of cohorts of commercial feedlot cattle, and to identify cattle demographic factors at feedlot arrival as potential sources of variance heterogeneity, accounting for cohort- and feedlot-level information in the data structure. An operational dataset compiled from 24,050 cohorts from 25 U. S. commercial feedlots in 2005 and 2006 was used for this study. Inference was based on a hierarchical Bayesian model implemented with Markov chain Monte Carlo, whereby cohorts were modeled at the residual level and feedlot-year clusters were modeled as random effects. Forward model selection based on deviance information criteria was used to screen potentially important explanatory variables for heteroskedasticity at cohort- and feedlot-year levels. The Bayesian modeling framework was preferred as it naturally accommodates the inherently hierarchical structure of feedlot data whereby cohorts are nested within feedlot-year clusters. Evidence for heterogeneity of variance components of ADG was substantial and primarily concentrated at the cohort level. Feedlot-year specific effects were, by far, the greatest contributors to ADG heteroskedasticity among cohorts, with an estimated ∼12-fold change in dispersion between most and least extreme feedlot-year clusters. In addition, identifiable demographic factors associated with greater heterogeneity of cohort-level variance included smaller cohort sizes, fewer days on feed, and greater arrival BW, as well as feedlot arrival during summer months. These results support that heterogeneity of variances in ADG is prevalent in feedlot performance and indicate potential sources of heteroskedasticity. Further investigation of factors associated with heteroskedasticity in feedlot performance is warranted to increase consistency and uniformity in commercial beef cattle production and subsequent profitability.

Scattering of S waves diffracted at the core-mantle boundary: forward modelling

NASA Astrophysics Data System (ADS)

Emery, Valérie; Maupin, Valérie; Nataf, Henri-Claude

1999-11-01

The lowermost 200-300 km of the Earth's mantle, known as the D'' layer, is an extremely complex and heterogeneous region where transfer processes between the core and the mantle take place. Diffracted S waves propagate over large distances and are very sensitive to the velocity structure of this region. Strong variations of ampli-tudes and waveforms are observed on recordings from networks of broad-band seismic stations. We perform forward modelling of diffracted S waves in laterally heterogeneous structures in order to analyse whether or not these observations can be related to lateral inhomogeneities in D''. We combine the diffraction due to the core and the scattering due to small-scale volumetric heterogeneities (10-100 km) by coupling single scattering (Born approximation) with the Langer approximation, which describes Sdiff wave propagation. The influence on the direct as well as on the scattered wavefields of the CMB as well as of possible tunnelling in the core or in D'' is fully accounted for. The SH and the SV components of the diffracted waves are analysed, as well as their coupling. The modelling is applied in heterogeneous models with different geometries: isolated heterogeneities, vertical cylinders, horizontal inhomogeneities and random media. Amplitudes of scattered waves are weak and only velocity perturbations of the order of 10 per cent over a volume of 240 x 240 x 300 km3 produce visible effects on seismograms. The two polarizations of Sdiff have different radial sensitivities, the SH components being more sensitive to heterogeneities closer to the CMB. However, we do not observe significant time-shifts between the two components similar to those produced by anisotropy. The long-period Sdiff have a poor lateral resolution and average the velocity perturbations in their Fresnel zone. Random small-scale heterogeneities with +/- 10 per cent velocity contrast in the layer therefore have little effect on Sdiff, in contrast to their effect on PKIKP.

Ozone impacts of gas-aerosol uptake in global chemistry transport models

NASA Astrophysics Data System (ADS)

Stadtler, Scarlet; Simpson, David; Schröder, Sabine; Taraborrelli, Domenico; Bott, Andreas; Schultz, Martin

2018-03-01

The impact of six heterogeneous gas-aerosol uptake reactions on tropospheric ozone and nitrogen species was studied using two chemical transport models, the Meteorological Synthesizing Centre-West of the European Monitoring and Evaluation Programme (EMEP MSC-W) and the European Centre Hamburg general circulation model combined with versions of the Hamburg Aerosol Model and Model for Ozone and Related chemical Tracers (ECHAM-HAMMOZ). Species undergoing heterogeneous reactions in both models include N2O5, NO3, NO2, O3, HNO3, and HO2. Since heterogeneous reactions take place at the aerosol surface area, the modelled surface area density (Sa) of both models was compared to a satellite product retrieving the surface area. This comparison shows a good agreement in global pattern and especially the capability of both models to capture the extreme aerosol loadings in east Asia. The impact of the heterogeneous reactions was evaluated by the simulation of a reference run containing all heterogeneous reactions and several sensitivity runs. One reaction was turned off in each sensitivity run to compare it with the reference run. The analysis of the sensitivity runs confirms that the globally most important heterogeneous reaction is the one of N2O5. Nevertheless, NO2, HNO3, and HO2 heterogeneous reactions gain relevance particularly in east Asia due to the presence of high NOx concentrations and high Sa in the same region. The heterogeneous reaction of O3 itself on dust is of minor relevance compared to the other heterogeneous reactions. The impacts of the N2O5 reactions show strong seasonal variations, with the biggest impacts on O3 in springtime when photochemical reactions are active and N2O5 levels still high. Evaluation of the models with northern hemispheric ozone surface observations yields a better agreement of the models with observations in terms of concentration levels, variability, and temporal correlations at most sites when the heterogeneous reactions are incorporated. Our results are loosely consistent with results from earlier studies, although the magnitude of changes induced by N2O5 reaction is at the low end of estimates, which seems to fit a trend, whereby the more recent the study the lower the impacts of these reactions.

Associations of occupational standing with musculoskeletal symptoms: a systematic review with meta-analysis.

PubMed

Coenen, Pieter; Willenberg, Lisa; Parry, Sharon; Shi, Joyce W; Romero, Lorena; Blackwood, Diana M; Maher, Christopher G; Healy, Genevieve N; Dunstan, David W; Straker, Leon M

2018-02-01

Given the high exposure to occupational standing in specific occupations, and recent initiatives to encourage intermittent standing among white-collar workers, a better understanding of the potential health consequences of occupational standing is required. We aimed to review and quantify the epidemiological evidence on associations of occupational standing with musculoskeletal symptoms. A systematic review was performed. Data from included articles were extracted and described, and meta-analyses conducted when data were sufficiently homogeneous. Electronic databases were systematically searched. Peer-reviewed articles on occupational standing and musculoskeletal symptoms from epidemiological studies were identified. Of the 11 750 articles screened, 50 articles reporting 49 studies were included (45 cross-sectional and 5 longitudinal; n=88 158 participants) describing the associations of occupational standing with musculoskeletal symptoms, including low-back (39 articles), lower extremity (14 articles) and upper extremity (18 articles) symptoms. In the meta-analysis, 'substantial' (>4 hours/workday) occupational standing was associated with the occurrence of low-back symptoms (pooled OR (95% CI) 1.31 (1.10 to 1.56)). Evidence on lower and upper extremity symptoms was too heterogeneous for meta-analyses. The majority of included studies reported statistically significant detrimental associations of occupational standing with lower extremity, but not with upper extremity symptoms. The evidence suggests that substantial occupational standing is associated with the occurrence of low-back and (inconclusively) lower extremity symptoms, but there may not be such an association with upper extremity symptoms. However, these conclusions are tentative as only limited evidence was found from high-quality, longitudinal studies with fully adjusted models using objective measures of standing. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Impacts of climate change on precipitation and discharge extremes through the use of statistical downscaling approaches in a Mediterranean basin.

PubMed

Piras, Monica; Mascaro, Giuseppe; Deidda, Roberto; Vivoni, Enrique R

2016-02-01

Mediterranean region is characterized by high precipitation variability often enhanced by orography, with strong seasonality and large inter-annual fluctuations, and by high heterogeneity of terrain and land surface properties. As a consequence, catchments in this area are often prone to the occurrence of hydrometeorological extremes, including storms, floods and flash-floods. A number of climate studies focused in the Mediterranean region predict that extreme events will occur with higher intensity and frequency, thus requiring further analyses to assess their effect at the land surface, particularly in small- and medium-sized watersheds. In this study, climate and hydrologic simulations produced within the Climate Induced Changes on the Hydrology of Mediterranean Basins (CLIMB) EU FP7 research project were used to analyze how precipitation extremes propagate into discharge extremes in the Rio Mannu basin (472.5km(2)), located in Sardinia, Italy. The basin hydrologic response to climate forcings in a reference (1971-2000) and a future (2041-2070) period was simulated through the combined use of a set of global and regional climate models, statistical downscaling techniques, and a process based distributed hydrologic model. We analyzed and compared the distribution of annual maxima extracted from hourly and daily precipitation and peak discharge time series, simulated by the hydrologic model under climate forcing. For this aim, yearly maxima were fit by the Generalized Extreme Value (GEV) distribution using a regional approach. Next, we discussed commonality and contrasting behaviors of precipitation and discharge maxima distributions to better understand how hydrological transformations impact propagation of extremes. Finally, we show how rainfall statistical downscaling algorithms produce more reliable forcings for hydrological models than coarse climate model outputs. Copyright © 2015 Elsevier B.V. All rights reserved.

No evidence of the effect of extreme weather events on annual occurrence of four groups of ectothermic species.

PubMed

Malinowska, Agnieszka H; van Strien, Arco J; Verboom, Jana; WallisdeVries, Michiel F; Opdam, Paul

2014-01-01

Weather extremes may have strong effects on biodiversity, as known from theoretical and modelling studies. Predicted negative effects of increased weather variation are found only for a few species, mostly plants and birds in empirical studies. Therefore, we investigated correlations between weather variability and patterns in occupancy, local colonisations and local extinctions (metapopulation metrics) across four groups of ectotherms: Odonata, Orthoptera, Lepidoptera, and Reptilia. We analysed data of 134 species on a 1×1 km-grid base, collected in the last 20 years from the Netherlands, combining standardised data and opportunistic data. We applied dynamic site-occupancy models and used the results as input for analyses of (i) trends in distribution patterns, (ii) the effect of temperature on colonisation and persistence probability, and (iii) the effect of years with extreme weather on all the three metapopulation metrics. All groups, except butterflies, showed more positive than negative trends in metapopulation metrics. We did not find evidence that the probability of colonisation or persistence increases with temperature nor that extreme weather events are reflected in higher extinction risks. We could not prove that weather extremes have visible and consistent negative effects on ectothermic species in temperate northern hemisphere. These findings do not confirm the general prediction that increased weather variability imperils biodiversity. We conclude that weather extremes might not be ecologically relevant for the majority of species. Populations might be buffered against weather variation (e.g. by habitat heterogeneity), or other factors might be masking the effects (e.g. availability and quality of habitat). Consequently, we postulate that weather extremes have less, or different, impact in real world metapopulations than theory and models suggest.

No Evidence of the Effect of Extreme Weather Events on Annual Occurrence of Four Groups of Ectothermic Species

PubMed Central

Malinowska, Agnieszka H.; van Strien, Arco J.; Verboom, Jana; WallisdeVries, Michiel F.; Opdam, Paul

2014-01-01

Weather extremes may have strong effects on biodiversity, as known from theoretical and modelling studies. Predicted negative effects of increased weather variation are found only for a few species, mostly plants and birds in empirical studies. Therefore, we investigated correlations between weather variability and patterns in occupancy, local colonisations and local extinctions (metapopulation metrics) across four groups of ectotherms: Odonata, Orthoptera, Lepidoptera, and Reptilia. We analysed data of 134 species on a 1×1 km-grid base, collected in the last 20 years from the Netherlands, combining standardised data and opportunistic data. We applied dynamic site-occupancy models and used the results as input for analyses of (i) trends in distribution patterns, (ii) the effect of temperature on colonisation and persistence probability, and (iii) the effect of years with extreme weather on all the three metapopulation metrics. All groups, except butterflies, showed more positive than negative trends in metapopulation metrics. We did not find evidence that the probability of colonisation or persistence increases with temperature nor that extreme weather events are reflected in higher extinction risks. We could not prove that weather extremes have visible and consistent negative effects on ectothermic species in temperate northern hemisphere. These findings do not confirm the general prediction that increased weather variability imperils biodiversity. We conclude that weather extremes might not be ecologically relevant for the majority of species. Populations might be buffered against weather variation (e.g. by habitat heterogeneity), or other factors might be masking the effects (e.g. availability and quality of habitat). Consequently, we postulate that weather extremes have less, or different, impact in real world metapopulations than theory and models suggest. PMID:25330414

Cost Per Additional Responder Associated With Ixekizumab and Etanercept in the Treatment of Moderate-to-Severe Psoriasis.

PubMed

Feldman, Steven R; Foster, Shonda A; Zhu, Baojin; Burge, Russel; Al Sawah, Sarah; Goldblum, Orin M

2017-12-01

BACKGROUND: Newer psoriasis treatments can achieve greater levels of efficacy than older systemic therapies; however, current psoriasis costs are substantial. We sought to estimate costs per additional responder associated with ixekizumab and etanercept, versus placebo, using efficacy data from phase 3 clinical trials (UNCOVER-2 and UNCOVER-3). METHODS: In UNCOVER-2/UNCOVER-3, patients received subcutaneous placebo, etanercept 50 mg twice weekly (BIW), or ixekizumab one 80 mg injection every 2 weeks (Q2W) after a 160-mg starting dose. Twelve-week induction-phase Psoriasis Area and Severity Index (PASI) 75, PASI 90, and PASI 100 response rates for ixekizumab, etanercept, and placebo were obtained from pooled data from the overall and United States (US) subgroup intention-to-treat (ITT) populations, and used to calculate numbers needed to treat (NNTs) to achieve one additional PASI 75, PASI 90, or PASI 100 response for ixekizumab Q2W and etanercept BIW versus placebo. Twelve-week drug costs per patient were calculated based on the UNCOVER-2/UNCOVER-3 dosing schedule and wholesale acquisition costs. Mean costs per additional responder for PASI 75, PASI 90, and PASI 100 for each treatment versus placebo were calculated for pooled UN-COVER-2/UNCOVER-3 overall and US subgroup ITT populations. RESULTS: Pooled overall ITT population: costs per additional PASI 75, PASI 90, or PASI 100 responder were US $37,540, US $46,299, or US $80,710 for ixekizumab Q2W and US $57,533, US $120,720, or US $404,695 for etanercept BIW, respectively. US subgroup ITT population: costs per additional PASI 75, PASI 90, or PASI 100 responder were US $38,165, US $49,740, or US $93,536 for ixekizumab Q2W and US $69,580, US $140,881, or US $631,875 for etanercept BIW, respectively. CONCLUSIONS: Twelve-week costs per additional responder were lower for ixekizumab Q2W than for etanercept BIW across all levels of clearance (PASI 75, PASI 90, and PASI 100) in the pooled UNCOVER-2/UNCOVER-3 overall and US subgroup ITT populations.

C, N, and O Isotopic Heterogeneities in Low-density Supernova Graphite Grains from Orgueil

NASA Astrophysics Data System (ADS)

Groopman, Evan; Bernatowicz, Thomas; Zinner, Ernst

2012-07-01

We report on the results of NanoSIMS isotope imaging of low-density supernova graphite grains from the Orgueil meteorite. 70 nm thick microtomed sections of three supernova graphite grains were deposited on Si wafers and isotopically imaged in the NanoSIMS. These sections contain hotspots of excesses in 18O and 15N, which are spatially well correlated, and are likely carried by internal TiC subgrains. These hotspots are considerably more enriched in 18O and 15N than the host graphite grain. Correlations between 18O and 15N excesses indicate that the grains incorporated material from the He/C supernova zone. Isotope images of the surfaces of some grains show heterogeneities in their N and O isotope compositions, with extreme excesses in 15N and 18O. In the microtome sections, we also observe two types of heterogeneities in the grains' C isotopic compositions: smooth, radial gradients in 12C/13C, with this ratio trending toward solar with increasing radius; and highly anomalous pockets up to 2 μm in size with 12C/13C Gt solar that are located near the centers of the grain sections. Partial isotopic equilibration does not likely explain the C isotopic heterogeneities. These grains and their constituent parts probably formed in a stellar environment with changing isotopic composition.

The Biot coefficient for a low permeability heterogeneous limestone

NASA Astrophysics Data System (ADS)

Selvadurai, A. P. S.

2018-04-01

This paper presents the experimental and theoretical developments used to estimate the Biot coefficient for the heterogeneous Cobourg Limestone, which is characterized by its very low permeability. The coefficient forms an important component of the Biot poroelastic model that is used to examine coupled hydro-mechanical and thermo-hydro-mechanical processes in the fluid-saturated Cobourg Limestone. The constraints imposed by both the heterogeneous fabric and its extremely low intact permeability [K \\in (10^{-23},10^{-20}) m2 ] require the development of alternative approaches to estimate the Biot coefficient. Large specimen bench-scale triaxial tests (150 mm diameter and 300 mm long) that account for the scale of the heterogeneous fabric are complemented by results for the volume fraction-based mineralogical composition derived from XRD measurements. The compressibility of the solid phase is based on theoretical developments proposed in the mechanics of multi-phasic elastic materials. An appeal to the theory of multi-phasic elastic solids is the only feasible approach for examining the compressibility of the solid phase. The presence of a number of mineral species necessitates the use of the theories of Voigt, Reuss and Hill along with the theories proposed by Hashin and Shtrikman for developing bounds for the compressibility of the multi-phasic geologic material composing the skeletal fabric. The analytical estimates for the Biot coefficient for the Cobourg Limestone are compared with results for similar low permeability rocks reported in the literature.

An Efficient Multiscale Finite-Element Method for Frequency-Domain Seismic Wave Propagation

DOE PAGES

Gao, Kai; Fu, Shubin; Chung, Eric T.

2018-02-13

The frequency-domain seismic-wave equation, that is, the Helmholtz equation, has many important applications in seismological studies, yet is very challenging to solve, particularly for large geological models. Iterative solvers, domain decomposition, or parallel strategies can partially alleviate the computational burden, but these approaches may still encounter nontrivial difficulties in complex geological models where a sufficiently fine mesh is required to represent the fine-scale heterogeneities. We develop a novel numerical method to solve the frequency-domain acoustic wave equation on the basis of the multiscale finite-element theory. We discretize a heterogeneous model with a coarse mesh and employ carefully constructed high-order multiscalemore » basis functions to form the basis space for the coarse mesh. Solved from medium- and frequency-dependent local problems, these multiscale basis functions can effectively capture themedium’s fine-scale heterogeneity and the source’s frequency information, leading to a discrete system matrix with a much smaller dimension compared with those from conventional methods.We then obtain an accurate solution to the acoustic Helmholtz equation by solving only a small linear system instead of a large linear system constructed on the fine mesh in conventional methods.We verify our new method using several models of complicated heterogeneities, and the results show that our new multiscale method can solve the Helmholtz equation in complex models with high accuracy and extremely low computational costs.« less

An Efficient Multiscale Finite-Element Method for Frequency-Domain Seismic Wave Propagation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Kai; Fu, Shubin; Chung, Eric T.

The frequency-domain seismic-wave equation, that is, the Helmholtz equation, has many important applications in seismological studies, yet is very challenging to solve, particularly for large geological models. Iterative solvers, domain decomposition, or parallel strategies can partially alleviate the computational burden, but these approaches may still encounter nontrivial difficulties in complex geological models where a sufficiently fine mesh is required to represent the fine-scale heterogeneities. We develop a novel numerical method to solve the frequency-domain acoustic wave equation on the basis of the multiscale finite-element theory. We discretize a heterogeneous model with a coarse mesh and employ carefully constructed high-order multiscalemore » basis functions to form the basis space for the coarse mesh. Solved from medium- and frequency-dependent local problems, these multiscale basis functions can effectively capture themedium’s fine-scale heterogeneity and the source’s frequency information, leading to a discrete system matrix with a much smaller dimension compared with those from conventional methods.We then obtain an accurate solution to the acoustic Helmholtz equation by solving only a small linear system instead of a large linear system constructed on the fine mesh in conventional methods.We verify our new method using several models of complicated heterogeneities, and the results show that our new multiscale method can solve the Helmholtz equation in complex models with high accuracy and extremely low computational costs.« less

Solar fuels generation and molecular systems: is it homogeneous or heterogeneous catalysis?

PubMed

Artero, Vincent; Fontecave, Marc

2013-03-21

Catalysis is a key enabling technology for solar fuel generation. A number of catalytic systems, either molecular/homogeneous or solid/heterogeneous, have been developed during the last few decades for both the reductive and oxidative multi-electron reactions required for fuel production from water or CO(2) as renewable raw materials. While allowing for a fine tuning of the catalytic properties through ligand design, molecular approaches are frequently criticized because of the inherent fragility of the resulting catalysts, when exposed to extreme redox potentials. In a number of cases, it has been clearly established that the true catalytic species is heterogeneous in nature, arising from the transformation of the initial molecular species, which should rather be considered as a pre-catalyst. Whether such a situation is general or not is a matter of debate in the community. In this review, covering water oxidation and reduction catalysts, involving noble and non-noble metal ions, we limit our discussion to the cases in which this issue has been directly and properly addressed as well as those requiring more confirmation. The methodologies proposed for discriminating homogeneous and heterogeneous catalysis are inspired in part by those previously discussed by Finke in the case of homogeneous hydrogenation reaction in organometallic chemistry [J. A. Widegren and R. G. Finke, J. Mol. Catal. A, 2003, 198, 317-341].

Low-energy Control of Electrical Turbulence in the Heart

PubMed Central

Luther, Stefan; Fenton, Flavio H.; Kornreich, Bruce G.; Squires, Amgad; Bittihn, Philip; Hornung, Daniel; Zabel, Markus; Flanders, James; Gladuli, Andrea; Campoy, Luis; Cherry, Elizabeth M.; Luther, Gisa; Hasenfuss, Gerd; Krinsky, Valentin I.; Pumir, Alain; Gilmour, Robert F.; Bodenschatz, Eberhard

2011-01-01

Controlling the complex spatio-temporal dynamics underlying life-threatening cardiac arrhythmias such as fibrillation is extremely difficult due to the nonlinear interaction of excitation waves within a heterogeneous anatomical substrate1–4. Lacking a better strategy, strong, globally resetting electrical shocks remain the only reliable treatment for cardiac fibrillation5–7. Here, we establish the relation between the response of the tissue to an electric field and the spatial distribution of heterogeneities of the scale-free coronary vascular structure. We show that in response to a pulsed electric field E, these heterogeneities serve as nucleation sites for the generation of intramural electrical waves with a source density ρ(E), and a characteristic time τ for tissue depolarization that obeys a power law τ∝Eα. These intramural wave sources permit targeting of electrical turbulence near the cores of the vortices of electrical activity that drive complex fibrillatory dynamics. We show in vitro that simultaneous and direct access to multiple vortex cores results in rapid synchronization of cardiac tissue and therefore efficient termination of fibrillation. Using this novel control strategy, we demonstrate, for the first time, low-energy termination of fibrillation in vivo. Our results give new insights into the mechanisms and dynamics underlying the control of spatio-temporal chaos in heterogeneous excitable media and at the same time provide new research perspectives towards alternative, life-saving low-energy defibrillation techniques. PMID:21753855

Heterogeneity of Loss Aversion in Pathological Gambling.

PubMed

Takeuchi, Hideaki; Kawada, Ryosaku; Tsurumi, Kosuke; Yokoyama, Naoto; Takemura, Ariyoshi; Murao, Takuro; Murai, Toshiya; Takahashi, Hidehiko

2016-12-01

Pathological gambling (PG) is characterized by continual repeated gambling behavior despite negative consequences. PG is considered to be a disorder of altered decision-making under risk, and behavioral economics tools were utilized by studies on decision-making under risk. At the same time, PG was suggested to be a heterogeneous disorder in terms of personality traits as well as risk attitude. We aimed to examine the heterogeneity of PG in terms of loss aversion, which means that a loss is subjectively felt to be larger than the same amount of gain. Thirty-one male PG subjects and 26 male healthy control (HC) subjects underwent a behavioral economics task for estimation of loss aversion and personality traits assessment. Although loss aversion in PG subjects was not significantly different from that in HC subjects, distributions of loss aversion differed between PG and HC subjects. HC subjects were uniformly classified into three levels (low, middle, high) of loss aversion, whereas PG subjects were mostly classified into the two extremes, and few PG subjects were classified into the middle range. PG subjects with low and high loss aversion showed a significant difference in anxiety, excitement-seeking and craving intensity. Our study suggested that PG was a heterogeneous disorder in terms of loss aversion. This result might be useful for understanding cognitive and neurobiological mechanisms and the establishment of treatment strategies for PG.

Biogeochemical Heterogeneity in Mars Analog Soils from the Atacama Desert

NASA Astrophysics Data System (ADS)

Claire, M.; Shirey, B.; Brown, M.; Anderson, D.; Van Mourik, M.

2014-12-01

Water is ubiquitous on Earth and plays a fundamental role in all aspects of biogeochemical cycling. Our existence on an aqua planet hampers our ability to interpret a planet like Mars where it may not have rained for a billion years. Soils from the hyperarid core of Chile's Atacama Desert may represent the closest geochemical analog to Martian soils, as this region has the lowest precipitation on Earth. The extreme lack of rainfall (a few mm per decade) limits both weathering and biological activity to the point where soils are effectively sterile. Oxidized end products of atmospheric chemistry such as nitrate and perchlorate build up to values approaching those measured on Mars by NASA's Phoenix Lander. In June 2012, we collected soil samples from 8 locations along an aridity gradient from the hyperarid core of the Atacama (rainfall < 1 mm/yr) towards the arid (5-100 mm/yr) surrounding areas where microbial community activity is sufficient to support the hardiest of desert plant species. Field observations indicate that microbial activity and geochemical heterogeneity are anti-correlated. We will present our quantitative results coupling geochemical heterogeneity (salt concentrations, org C/N, trace metals) and microbial community activity (TRFLP, nitrogen cycling) along this transect, and argue that geochemical heterogeneity (which could be measured by a rover or lander on Mars) may be a proxy for lifeless soils.

Integrating transient heterogeneity of non-photochemical quenching in shade-grown heterobaric leaves of avocado (Persea americana L.): responses to CO2 concentration, stomatal occlusion, dehydration and relative humidity.

PubMed

Takayama, Kotaro; King, Diana; Robinson, Sharon A; Osmond, Barry

2013-11-01

Long-lived shade leaves of avocado had extremely low rates of photosynthesis. Gas exchange measurements of photosynthesis were of limited use, so we resorted to Chl fluorescence imaging (CFI) and spot measurements to evaluate photosynthetic electron transport rates (ETRs) and non-photochemical quenching (NPQ). Imaging revealed a remarkable transient heterogeneity of NPQ during photosynthetic induction in these hypostomatous, heterobaric leaves, but was adequately integrated by spot measurements, despite long-lasting artifacts from repeated saturating flashes during assays. Major veins (mid-vein, first- and second-order veins) defined areas of more static large-scale heterogeneous NPQ, with more dynamic small-scale heterogeneity most strongly expressed in mesophyll cells between third- and fourth-order veins. Both responded to external CO2 concentration ([CO2]), occlusion of stomata with Vaseline™, leaf dehydration and relative humidity (RH). We interpreted these responses in terms of independent behavior of stomata in adjacent areoles that was largely expressed through CO2-limited photosynthesis. Heterogeneity was most pronounced and prolonged in the absence of net CO2 fixation in 100 p.p.m. [CO2] when respiratory and photorespiratory CO2 cycling constrained the inferred ETR to ~75% of values in 400 or 700 p.p.m. [CO2]. Likewise, sustained higher NPQ under Vaseline™, after dehydration or at low RH, also restricted ETR to ~75% of control values. Low NPQ in chloroplast-containing cells adjacent to major veins but remote from stomata suggested internal sources of high [CO2] in these tissues.

New Insights into Auroral Particle Acceleration via Coordinated Optical-Radar Networks

NASA Astrophysics Data System (ADS)

Hirsch, M.

2016-12-01

The efficacy of instruments synthesized from heterogeneous sensor networks is increasingly being realized in fielded science observation systems. New insights into the finest spatio-temporal scales of ground-observable ionospheric physics are realized by coupling low-level data from fixed legacy instruments with mobile and portable sensors. In particular, turbulent ionospheric events give enhanced radar returns more than three orders of magnitude larger than typical incoherent plasma observations. Radar integration times for the Poker Flat Incoherent Scatter Radar (PFISR) can thereby be shrunk from order 100 second integration time down to order 100 millisecond integration time for the ion line. Auroral optical observations with 20 millisecond cadence synchronized in absolute time with the radar help uncover plausible particle acceleration processes for the highly dynamic aurora often associated with Langmuir turbulence. Quantitative analysis of coherent radar returns combined with a physics-based model yielding optical volume emission rate profiles vs. differential number flux input of precipitating particles into the ionosphere yield plausibility estimates for a particular auroral acceleration process type. Tabulated results from a survey of auroral events where the Boston University High Speed Auroral Tomography system operated simultaneously with PFISR are presented. Context is given to the narrow-field HiST observations by the Poker Flat Digital All-Sky Camera and THEMIS GBO ASI network. Recent advances in high-rate (order 100 millisecond) plasma line ISR observations (100x improvement in temporal resolution) will contribute to future coordinated observations. ISR beam pattern and pulse parameter configurations favorable for future coordinated optical-ISR experiments are proposed in light of recent research uncovering the criticality of aspect angle to ISR-observable physics. High-rate scientist-developed GPS TEC receivers are expected to contribute additional high resolution observations to such experiments.

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

PubMed

Schmitz, Roland; Wright, George W; Huang, Da Wei; Johnson, Calvin A; Phelan, James D; Wang, James Q; Roulland, Sandrine; Kasbekar, Monica; Young, Ryan M; Shaffer, Arthur L; Hodson, Daniel J; Xiao, Wenming; Yu, Xin; Yang, Yandan; Zhao, Hong; Xu, Weihong; Liu, Xuelu; Zhou, Bin; Du, Wei; Chan, Wing C; Jaffe, Elaine S; Gascoyne, Randy D; Connors, Joseph M; Campo, Elias; Lopez-Guillermo, Armando; Rosenwald, Andreas; Ott, German; Delabie, Jan; Rimsza, Lisa M; Tay Kuang Wei, Kevin; Zelenetz, Andrew D; Leonard, John P; Bartlett, Nancy L; Tran, Bao; Shetty, Jyoti; Zhao, Yongmei; Soppet, Dan R; Pittaluga, Stefania; Wilson, Wyndham H; Staudt, Louis M

2018-04-12

Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88 L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition. We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).

At the heart of the problem - A person-centred, developmental perspective on the link between alcohol consumption and cardio-vascular events.

PubMed

Lima Passos, Valéria; Klijn, Sven; van Zandvoort, Kevin; Abidi, Latifa; Lemmens, Paul

2017-04-01

The cardio-protective effect of alcohol has been the subject of a long-standing scientific controversy. Emerging evidence remains equivocal, as the validity of the dose-dependent J-shape association is tainted by conceptual, theoretical and methodological problems. A major impediment for a resolution on the matter is the lack of a life-long developmental approach to pinpoint alcohol's specific impact on the risk for cardio-vascular events (CVE). Using retrospective and prospective individual-level data of alcohol consumption (AC) we applied a model-based clustering technique to uncover life-course trajectories of AC and explored their links to CVE. Data stemmed from a random sub-cohort of a large-scale, longitudinal study conducted in the Netherlands (N=2288). Group Based Trajectory Model (GBTM) was applied to extract distinct progressions of AC over time. Stratified by sex, the association between the developmental trajectories and CVE was examined with multiple logistic regression models, with adjustment for traditional risk factors. GBTM analysis laid bare the heterogeneity of AC dynamics over the life-course, reiterating sex differences in drinking habits and CVE risk. AC temporal behaviors during adolescence and adulthood were diverse, but showed relative stability in in middle-age and elderly years. For males, adjusted odds for CVE differed among the uncovered developmental classes. The findings elicited supportive evidence for a J-shape, but with a new twist. Besides moderation the results indicate that onset, timing, duration and stability of AC over the life-course are major aspects to be accounted for when attempting to elucidate alcohol's cardio-vascular role. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

An analysis of ranibizumab treatment and visual outcomes in real-world settings: the UNCOVER study.

PubMed

Eldem, Bora; Lai, Timothy Y Y; Ngah, Nor Fariza; Vote, Brendan; Yu, Hyeong Gon; Fabre, Alban; Backer, Arthur; Clunas, Nathan J

2018-05-01

To describe intravitreal ranibizumab treatment frequency, clinical monitoring, and visual outcomes (including mean central retinal thickness [CRT] and visual acuity [VA] changes from baseline) in neovascular age-related macular degeneration (nAMD) in real-world settings across three ranibizumab reimbursement scenarios in the Middle East, North Africa, and the Asia-Pacific region. Non-interventional multicenter historical cohort study of intravitreal ranibizumab use for nAMD in routine clinical practice between April 2010 and April 2013. Eligible patients were diagnosed with nAMD, received at least one intravitreal ranibizumab injection during the study period, and had been observed for a minimum of 1 year (up to 3 years). Reimbursement scenarios were defined as self-paid, partially-reimbursed, and fully-reimbursed. More than three-fourths (n = 2521) of the analysis population was partially-reimbursed for ranibizumab, while 16.4% (n = 532) was fully-reimbursed, and 5.8% was self-paid (n = 188). The average annual ranibizumab injection frequency was 4.1 injections in the partially-reimbursed, 4.7 in the fully-reimbursed and 2.6 in the self-paid populations. The average clinical monitoring frequency was estimated to be 6.7 visits/year, with similar frequencies observed across reimbursement categories. On average, patients experienced VA reduction of -0.7 letters and a decrease in CRT of -44.4 μm. The greatest mean CRT change was observed in the self-paid group, with -92.6 μm. UNCOVER included a large, heterogeneous ranibizumab-treated nAMD population in real-world settings. Patients in all reimbursement scenarios attained vision stability on average, indicating control of disease activity.

"An unspoken world of unspoken things": a study identifying and exploring core beliefs underlying self-stigma among people living with HIV and AIDS in Ireland.

PubMed

France, Nadine Ferris; Mcdonald, Steve H; Conroy, Ronan R; Byrne, Elaine; Mallouris, Chris; Hodgson, Ian; Larkan, Fiona N

2015-01-01

Human immunodeficiency virus (HIV) related self-stigma--negative self-judgements resulting in shame, worthlessness and self-blame - negatively influences access to care and treatment, and overall quality of life for people living with HIV (PLHIV). Despite evidence that high levels of self-stigma exist among PLHIV, and is experienced to a far greater extent than stigma received from the broader community, there is a paucity of research aimed at understanding causes and functions of self-stigma, and an absence of interventions to mitigate its harmful effects. Understanding the core beliefs underlying self-stigma is therefore essential. This pilot study used a qualitative approach to analyse interviews and written statements to uncover core beliefs underlying self-stigma, the functions thereof, and strategies used to overcome it, among a heterogeneous group of PLHIV in Ireland. Core beliefs underlying HIV-related self-stigma were uncovered and grouped into four categories: disclosure; sexuality and sexual pleasure; self-perception; and body, illness and death. Reported functions of self-stigma included contributing to maintaining a "victim" status; providing protection against stigma received from others; and justifying non-disclosure of HIV status. To cope with self-stigma, participants highlighted: community involvement and professional development; personal development; and connection to others and sense of belonging. Findings were also used to create a conceptual framework. This study helps fill identified gaps in knowledge about self-stigma as experienced by PLHIV. By understanding the core beliefs driving self-stigma, it will be possible to create targeted interventions to challenge and overcome such beliefs, supporting PLHIV to achieve improved wellbeing and lead productive lives free of self-limitation and self-judgement.

Statistical Extremes of Turbulence and a Cascade Generalisation of Euler's Gyroscope Equation

NASA Astrophysics Data System (ADS)

Tchiguirinskaia, Ioulia; Scherzer, Daniel

2016-04-01

Turbulence refers to a rather well defined hydrodynamical phenomenon uncovered by Reynolds. Nowadays, the word turbulence is used to designate the loss of order in many different geophysical fields and the related fundamental extreme variability of environmental data over a wide range of scales. Classical statistical techniques for estimating the extremes, being largely limited to statistical distributions, do not take into account the mechanisms generating such extreme variability. An alternative approaches to nonlinear variability are based on a fundamental property of the non-linear equations: scale invariance, which means that these equations are formally invariant under given scale transforms. Its specific framework is that of multifractals. In this framework extreme variability builds up scale by scale leading to non-classical statistics. Although multifractals are increasingly understood as a basic framework for handling such variability, there is still a gap between their potential and their actual use. In this presentation we discuss how to dealt with highly theoretical problems of mathematical physics together with a wide range of geophysical applications. We use Euler's gyroscope equation as a basic element in constructing a complex deterministic system that preserves not only the scale symmetry of the Navier-Stokes equations, but some more of their symmetries. Euler's equation has been not only the object of many theoretical investigations of the gyroscope device, but also generalised enough to become the basic equation of fluid mechanics. Therefore, there is no surprise that a cascade generalisation of this equation can be used to characterise the intermittency of turbulence, to better understand the links between the multifractal exponents and the structure of a simplified, but not simplistic, version of the Navier-Stokes equations. In a given way, this approach is similar to that of Lorenz, who studied how the flap of a butterfly wing could generate a cyclone with the help of a 3D ordinary differential system. Being well supported by the extensive numerical results, the cascade generalisation of Euler's gyroscope equation opens new horizons for predictability and predictions of processes having long-range dependences.

Evolution of scaling emergence in large-scale spatial epidemic spreading.

PubMed

Wang, Lin; Li, Xiang; Zhang, Yi-Qing; Zhang, Yan; Zhang, Kan

2011-01-01

Zipf's law and Heaps' law are two representatives of the scaling concepts, which play a significant role in the study of complexity science. The coexistence of the Zipf's law and the Heaps' law motivates different understandings on the dependence between these two scalings, which has still hardly been clarified. In this article, we observe an evolution process of the scalings: the Zipf's law and the Heaps' law are naturally shaped to coexist at the initial time, while the crossover comes with the emergence of their inconsistency at the larger time before reaching a stable state, where the Heaps' law still exists with the disappearance of strict Zipf's law. Such findings are illustrated with a scenario of large-scale spatial epidemic spreading, and the empirical results of pandemic disease support a universal analysis of the relation between the two laws regardless of the biological details of disease. Employing the United States domestic air transportation and demographic data to construct a metapopulation model for simulating the pandemic spread at the U.S. country level, we uncover that the broad heterogeneity of the infrastructure plays a key role in the evolution of scaling emergence. The analyses of large-scale spatial epidemic spreading help understand the temporal evolution of scalings, indicating the coexistence of the Zipf's law and the Heaps' law depends on the collective dynamics of epidemic processes, and the heterogeneity of epidemic spread indicates the significance of performing targeted containment strategies at the early time of a pandemic disease.

Salmonella Intracellular Lifestyles and Their Impact on Host-to-Host Transmission.

PubMed

Pucciarelli, M Graciela; García-Del Portillo, Francisco

2017-07-01

More than a century ago, infections by Salmonella were already associated with foodborne enteric diseases with high morbidity in humans and cattle. Intestinal inflammation and diarrhea are hallmarks of infections caused by nontyphoidal Salmonella serovars, and these pathologies facilitate pathogen transmission to the environment. In those early times, physicians and microbiologists also realized that typhoid and paratyphoid fever caused by some Salmonella serovars could be transmitted by "carriers," individuals outwardly healthy or at most suffering from some minor chronic complaint. In his pioneering study of the nontyphoidal serovar Typhimurium in 1967, Takeuchi published the first images of intracellular bacteria enclosed by membrane-bound vacuoles in the initial stages of the intestinal epithelium penetration. These compartments, called Salmonella -containing vacuoles, are highly dynamic phagosomes with differing biogenesis depending on the host cell type. Single-cell studies involving real-time imaging and gene expression profiling, together with new approaches based on genetic reporters sensitive to growth rate, have uncovered unprecedented heterogeneous responses in intracellular bacteria. Subpopulations of intracellular bacteria displaying fast, reduced, or no growth, as well as cytosolic and intravacuolar bacteria, have been reported in both in vitro and in vivo infection models. Recent investigations, most of them focused on the serovar Typhimurium, point to the selection of persisting bacteria inside macrophages or following an autophagy attack in fibroblasts. Here, we discuss these heterogeneous intracellular lifestyles and speculate on how these disparate behaviors may impact host-to-host transmissibility of Salmonella serovars.

Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas.

PubMed

Murakami, Masanori; Yoshimoto, Takanobu; Nakabayashi, Kazuhiko; Nakano, Yujiro; Fukaishi, Takahiro; Tsuchiya, Kyoichiro; Minami, Isao; Bouchi, Ryotaro; Okamura, Kohji; Fujii, Yasuhisa; Hashimoto, Koshi; Hata, Ken-Ichiro; Kihara, Kazunori; Ogawa, Yoshihiro

2017-10-01

The pathophysiology of aldosterone-producing adenomas (APAs) has been investigated via genetic approaches and the pathogenic significance of a series of somatic mutations, including KCNJ5 , has been uncovered. However, how the mutational status of an APA is associated with its molecular characteristics, including its transcriptome and methylome, has not been fully understood. This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with KCNJ5 mutations as opposed to those without KCNJ5 mutations, by comparing their transcriptome and methylome status. Cortisol-producing adenomas (CPAs) were used as reference. We conducted transcriptome and methylome analyses of 29 APAs with KCNJ5 mutations, 8 APAs without KCNJ5 mutations and 5 CPAs. Genome-wide gene expression and CpG methylation profiles were obtained from RNA and DNA samples extracted from these 42 adrenal tumors. Cluster analysis of the transcriptome and methylome revealed molecular heterogeneity in APAs depending on their mutational status. DNA hypomethylation and gene expression changes in Wnt signaling and inflammatory response pathways were characteristic of APAs with KCNJ5 mutations. Comparisons between transcriptome data from our APAs and that from normal adrenal cortex obtained from the Gene Expression Omnibus suggested similarities between APAs with KCNJ5 mutations and zona glomerulosa. The present study, which is based on transcriptome and methylome analyses, indicates the molecular heterogeneity of APAs depends on their mutational status. Here, we report the unique characteristics of APAs with KCNJ5 mutations. © 2017 Society for Endocrinology.

Conformational heterogeneity in closed and open states of the KcsA potassium channel in lipid bicelles

PubMed Central

Kim, Dorothy M.; Dikiy, Igor; Upadhyay, Vikrant; Posson, David J.

2016-01-01

The process of ion channel gating—opening and closing—involves local and global structural changes in the channel in response to external stimuli. Conformational changes depend on the energetic landscape that underlies the transition between closed and open states, which plays a key role in ion channel gating. For the prokaryotic, pH-gated potassium channel KcsA, closed and open states have been extensively studied using structural and functional methods, but the dynamics within each of these functional states as well as the transition between them is not as well understood. In this study, we used solution nuclear magnetic resonance (NMR) spectroscopy to investigate the conformational transitions within specific functional states of KcsA. We incorporated KcsA channels into lipid bicelles and stabilized them into a closed state by using either phosphatidylcholine lipids, known to favor the closed channel, or mutations designed to trap the channel shut by disulfide cross-linking. A distinct state, consistent with an open channel, was uncovered by the addition of cardiolipin lipids. Using selective amino acid labeling at locations within the channel that are known to move during gating, we observed at least two different slowly interconverting conformational states for both closed and open channels. The pH dependence of these conformations and the predictable disruptions to this dependence observed in mutant channels with altered pH sensing highlight the importance of conformational heterogeneity for KcsA gating. PMID:27432996

From “cracking the orthographic code” to “playing with language”: toward a usage-based foundation of the reading process

PubMed Central

Wallot, Sebastian

2014-01-01

The empirical study of reading dates back more than 125 years. But despite this long tradition, the scientific understanding of reading has made rather heterogeneous progress: many factors that influence the process of text reading have been uncovered, but theoretical explanations remain fragmented; no general theory pulls together the diverse findings. A handful of scholars have noted that properties thought to be at the core of the reading process do not actually generalize across different languages or from situations single-word reading to connected text reading. Such observations cast doubt on many of the traditional conceptions about reading. In this article, I suggest that the observed heterogeneity in the research is due to misguided conceptions about the reading process. Particularly problematic are the unrefined notions about meaning which undergird many reading theories: most psychological theories of reading implicitly assume a kind of elemental token semantics, where words serve as stable units of meaning in a text. This conception of meaning creates major conceptual problems. As an alternative, I argue that reading shoud be rather understood as a form of language use, which circumvents many of the conceptual problems and connects reading to a wider range of linguistic communication. Finally, drawing from Wittgenstein, the concept of “language games” is outlined as an approach to language use that can be operationalized scientifically to provide a new foundation for reading research. PMID:25202285

High degree of genetic differentiation in marine three-spined sticklebacks (Gasterosteus aculeatus).

PubMed

Defaveri, Jacquelin; Shikano, Takahito; Shimada, Yukinori; Merilä, Juha

2013-09-01

Populations of widespread marine organisms are typically characterized by a low degree of genetic differentiation in neutral genetic markers, but much less is known about differentiation in genes whose functional roles are associated with specific selection regimes. To uncover possible adaptive population divergence and heterogeneous genomic differentiation in marine three-spined sticklebacks (Gasterosteus aculeatus), we used a candidate gene-based genome-scan approach to analyse variability in 138 microsatellite loci located within/close to (<6 kb) functionally important genes in samples collected from ten geographic locations. The degree of genetic differentiation in markers classified as neutral or under balancing selection-as determined with several outlier detection methods-was low (F(ST) = 0.033 or 0.011, respectively), whereas average FST for directionally selected markers was significantly higher (F(ST) = 0.097). Clustering analyses provided support for genomic and geographic heterogeneity in selection: six genetic clusters were identified based on allele frequency differences in the directionally selected loci, whereas four were identified with the neutral loci. Allelic variation in several loci exhibited significant associations with environmental variables, supporting the conjecture that temperature and salinity, but not optic conditions, are important drivers of adaptive divergence among populations. In general, these results suggest that in spite of the high degree of physical connectivity and gene flow as inferred from neutral marker genes, marine stickleback populations are strongly genetically structured in loci associated with functionally relevant genes. © 2013 John Wiley & Sons Ltd.

Can the complementary relationship between actual and potential evaporation be used to quantify heatwaves?

NASA Astrophysics Data System (ADS)

Aminzadeh, Milad; Or, Dani

2017-04-01

Extreme climate events such as heatwaves with prolonged periods of high air temperatures have large environmental, social, and economic impacts ranging from crop failure to health and desiccation damages. Periods of low precipitation with high temperatures decrease soil moisture storage and thus affect surface energy partitioning. The heuristic concepts in the basis of the Complementary Relationship (CR) suggest that a fraction of radiative energy not used for evaporation contributes to increased sensible heat flux thus heats near-surface atmosphere. We have recently generalized the CR framework for spatially heterogeneous landscapes thereby enable prediction of actual evapotranspiration (ET) from routine atmospheric measurements. Capitalizing on the coupling between moisture availability, actual ET and sensible heat flux we propose using the CR to predict conditions conducive to rapid increase in regional sensible heat flux associated with the onset of extreme heatwaves. The proposed framework is evaluated using satellite surface temperature and FLUXNET data with newly derived metrics for the onset of heatwaves. The concepts could be extended to obtain new insights into the dynamics of more persistent climate extremes such as regional droughts.

Three decades of high-resolution coastal sea surface temperatures reveal more than warming.

PubMed

Lima, Fernando P; Wethey, David S

2012-02-28

Understanding and forecasting current and future consequences of coastal warming require a fine-scale assessment of the near-shore temperature changes. Here we show that despite the fact that 71% of the world's coastlines are significantly warming, rates of change have been highly heterogeneous both spatially and seasonally. We demonstrate that 46% of the coastlines have experienced a significant decrease in the frequency of extremely cold events, while extremely hot days are becoming more common in 38% of the area. Also, we show that the onset of the warm season is significantly advancing earlier in the year in 36% of the temperate coastal regions. More importantly, it is now possible to analyse local patterns within the global context, which is useful for a broad array of scientific fields, policy makers and general public.

Applying Incremental Sampling Methodology to Soils Containing Heterogeneously Distributed Metallic Residues to Improve Risk Analysis.

PubMed

Clausen, J L; Georgian, T; Gardner, K H; Douglas, T A

2018-01-01

This study compares conventional grab sampling to incremental sampling methodology (ISM) to characterize metal contamination at a military small-arms-range. Grab sample results had large variances, positively skewed non-normal distributions, extreme outliers, and poor agreement between duplicate samples even when samples were co-located within tens of centimeters of each other. The extreme outliers strongly influenced the grab sample means for the primary contaminants lead (Pb) and antinomy (Sb). In contrast, median and mean metal concentrations were similar for the ISM samples. ISM significantly reduced measurement uncertainty of estimates of the mean, increasing data quality (e.g., for environmental risk assessments) with fewer samples (e.g., decreasing total project costs). Based on Monte Carlo resampling simulations, grab sampling resulted in highly variable means and upper confidence limits of the mean relative to ISM.

The Italian primary school-size distribution and the city-size: a complex nexus

PubMed Central

Belmonte, Alessandro; Di Clemente, Riccardo; Buldyrev, Sergey V.

2014-01-01

We characterize the statistical law according to which Italian primary school-size distributes. We find that the school-size can be approximated by a log-normal distribution, with a fat lower tail that collects a large number of very small schools. The upper tail of the school-size distribution decreases exponentially and the growth rates are distributed with a Laplace PDF. These distributions are similar to those observed for firms and are consistent with a Bose-Einstein preferential attachment process. The body of the distribution features a bimodal shape suggesting some source of heterogeneity in the school organization that we uncover by an in-depth analysis of the relation between schools-size and city-size. We propose a novel cluster methodology and a new spatial interaction approach among schools which outline the variety of policies implemented in Italy. Different regional policies are also discussed shedding lights on the relation between policy and geographical features. PMID:24954714

Super-resolution and super-localization microscopy: A novel tool for imaging chemical and biological processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Bin

2015-01-01

Optical microscopy imaging of single molecules and single particles is an essential method for studying fundamental biological and chemical processes at the molecular and nanometer scale. The best spatial resolution (~ λ/2) achievable in traditional optical microscopy is governed by the diffraction of light. However, single molecule-based super-localization and super-resolution microscopy imaging techniques have emerged in the past decade. Individual molecules can be localized with nanometer scale accuracy and precision for studying of biological and chemical processes.This work uncovered the heterogeneous properties of the pore structures. In this dissertation, the coupling of molecular transport and catalytic reaction at the singlemore » molecule and single particle level in multilayer mesoporous nanocatalysts was elucidated. Most previous studies dealt with these two important phenomena separately. A fluorogenic oxidation reaction of non-fluorescent amplex red to highly fluorescent resorufin was tested. The diffusion behavior of single resorufin molecules in aligned nanopores was studied using total internal reflection fluorescence microscopy (TIRFM).« less

Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells.

PubMed

Darmanis, Spyros; Gallant, Caroline Julie; Marinescu, Voichita Dana; Niklasson, Mia; Segerman, Anna; Flamourakis, Georgios; Fredriksson, Simon; Assarsson, Erika; Lundberg, Martin; Nelander, Sven; Westermark, Bengt; Landegren, Ulf

2016-01-12

Significant advances have been made in methods to analyze genomes and transcriptomes of single cells, but to fully define cell states, proteins must also be accessed as central actors defining a cell's phenotype. Methods currently used to analyze endogenous protein expression in single cells are limited in specificity, throughput, or multiplex capability. Here, we present an approach to simultaneously and specifically interrogate large sets of protein and RNA targets in lysates from individual cells, enabling investigations of cell functions and responses. We applied our method to investigate the effects of BMP4, an experimental therapeutic agent, on early-passage glioblastoma cell cultures. We uncovered significant heterogeneity in responses to treatment at levels of RNA and protein, with a subset of cells reacting in a distinct manner to BMP4. Moreover, we found overall poor correlation between protein and RNA at the level of single cells, with proteins more accurately defining responses to treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Atomistics of vapour–liquid–solid nanowire growth

PubMed Central

Wang, Hailong; Zepeda-Ruiz, Luis A.; Gilmer, George H.; Upmanyu, Moneesh

2013-01-01

Vapour–liquid–solid route and its variants are routinely used for scalable synthesis of semiconducting nanowires, yet the fundamental growth processes remain unknown. Here we employ atomic-scale computations based on model potentials to study the stability and growth of gold-catalysed silicon nanowires. Equilibrium studies uncover segregation at the solid-like surface of the catalyst particle, a liquid AuSi droplet, and a silicon-rich droplet–nanowire interface enveloped by heterogeneous truncating facets. Supersaturation of the droplets leads to rapid one-dimensional growth on the truncating facets and much slower nucleation-controlled two-dimensional growth on the main facet. Surface diffusion is suppressed and the excess Si flux occurs through the droplet bulk which, together with the Si-rich interface and contact line, lowers the nucleation barrier on the main facet. The ensuing step flow is modified by Au diffusion away from the step edges. Our study highlights key interfacial characteristics for morphological and compositional control of semiconducting nanowire arrays. PMID:23752586

Egr-5 is a post-mitotic regulator of planarian epidermal differentiation

PubMed Central

Tu, Kimberly C; Cheng, Li-Chun; TK Vu, Hanh; Lange, Jeffrey J; McKinney, Sean A; Seidel, Chris W; Sánchez Alvarado, Alejandro

2015-01-01

Neoblasts are an abundant, heterogeneous population of adult stem cells (ASCs) that facilitate the maintenance of planarian tissues and organs, providing a powerful system to study ASC self-renewal and differentiation dynamics. It is unknown how the collective output of neoblasts transit through differentiation pathways to produce specific cell types. The planarian epidermis is a simple tissue that undergoes rapid turnover. We found that as epidermal progeny differentiate, they progress through multiple spatiotemporal transition states with distinct gene expression profiles. We also identified a conserved early growth response family transcription factor, egr-5, that is essential for epidermal differentiation. Disruption of epidermal integrity by egr-5 RNAi triggers a global stress response that induces the proliferation of neoblasts and the concomitant expansion of not only epidermal, but also multiple progenitor cell populations. Our results further establish the planarian epidermis as a novel paradigm to uncover the molecular mechanisms regulating ASC specification in vivo. DOI: http://dx.doi.org/10.7554/eLife.10501.001 PMID:26457503

Cross-visit tumor sub-segmentation and registration with outlier rejection for dynamic contrast-enhanced MRI time series data.

PubMed

Buonaccorsi, G A; Rose, C J; O'Connor, J P B; Roberts, C; Watson, Y; Jackson, A; Jayson, G C; Parker, G J M

2010-01-01

Clinical trials of anti-angiogenic and vascular-disrupting agents often use biomarkers derived from DCE-MRI, typically reporting whole-tumor summary statistics and so overlooking spatial parameter variations caused by tissue heterogeneity. We present a data-driven segmentation method comprising tracer-kinetic model-driven registration for motion correction, conversion from MR signal intensity to contrast agent concentration for cross-visit normalization, iterative principal components analysis for imputation of missing data and dimensionality reduction, and statistical outlier detection using the minimum covariance determinant to obtain a robust Mahalanobis distance. After applying these techniques we cluster in the principal components space using k-means. We present results from a clinical trial of a VEGF inhibitor, using time-series data selected because of problems due to motion and outlier time series. We obtained spatially-contiguous clusters that map to regions with distinct microvascular characteristics. This methodology has the potential to uncover localized effects in trials using DCE-MRI-based biomarkers.

Two-Dimensional Ordering of Solute Nanoclusters at a Close-Packed Stacking Fault: Modeling and Experimental Analysis

PubMed Central

Kimizuka, Hajime; Kurokawa, Shu; Yamaguchi, Akihiro; Sakai, Akira; Ogata, Shigenobu

2014-01-01

Predicting the equilibrium ordered structures at internal interfaces, especially in the case of nanometer-scale chemical heterogeneities, is an ongoing challenge in materials science. In this study, we established an ab-initio coarse-grained modeling technique for describing the phase-like behavior of a close-packed stacking-fault-type interface containing solute nanoclusters, which undergo a two-dimensional disorder-order transition, depending on the temperature and composition. Notably, this approach can predict the two-dimensional medium-range ordering in the nanocluster arrays realized in Mg-based alloys, in a manner consistent with scanning tunneling microscopy-based measurements. We predicted that the repulsively interacting solute-cluster system undergoes a continuous evolution into a highly ordered densely packed morphology while maintaining a high degree of six-fold orientational order, which is attributable mainly to an entropic effect. The uncovered interaction-dependent ordering properties may be useful for the design of nanostructured materials utilizing the self-organization of two-dimensional nanocluster arrays in the close-packed interfaces. PMID:25471232

Uncovering Novel Roles of Nonneuronal Cells in Body Weight Homeostasis and Obesity

PubMed Central

Argente, Jesús

2013-01-01

Glial cells, which constitute more than 50% of the mass of the central nervous system and greatly outnumber neurons, are at the vanguard of neuroendocrine research in metabolic control and obesity. Historically relegated to roles of structural support and protection, diverse functions have been gradually attributed to this heterogeneous class of cells with their protagonism in crescendo in all areas of neuroscience during the past decade. However, this dramatic increase in attention bestowed upon glial cells has also emphasized our vast lack of knowledge concerning many aspects of their physiological functions, let alone their participation in numerous pathologies. This minireview focuses on the recent advances in our understanding of how glial cells participate in the physiological regulation of appetite and systemic metabolism as well as their role in the pathophysiological response to poor nutrition and secondary complications associated with obesity. Moreover, we highlight some of the existing lagoons of knowledge in this increasingly important area of investigation. PMID:23798599

Cross-Population Joint Analysis of eQTLs: Fine Mapping and Functional Annotation

PubMed Central

Wen, Xiaoquan; Luca, Francesca; Pique-Regi, Roger

2015-01-01

Mapping expression quantitative trait loci (eQTLs) has been shown as a powerful tool to uncover the genetic underpinnings of many complex traits at molecular level. In this paper, we present an integrative analysis approach that leverages eQTL data collected from multiple population groups. In particular, our approach effectively identifies multiple independent cis-eQTL signals that are consistent across populations, accounting for population heterogeneity in allele frequencies and linkage disequilibrium patterns. Furthermore, by integrating genomic annotations, our analysis framework enables high-resolution functional analysis of eQTLs. We applied our statistical approach to analyze the GEUVADIS data consisting of samples from five population groups. From this analysis, we concluded that i) jointly analysis across population groups greatly improves the power of eQTL discovery and the resolution of fine mapping of causal eQTL ii) many genes harbor multiple independent eQTLs in their cis regions iii) genetic variants that disrupt transcription factor binding are significantly enriched in eQTLs (p-value = 4.93 × 10-22). PMID:25906321

Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer.

PubMed

Francavilla, Chiara; Lupia, Michela; Tsafou, Kalliopi; Villa, Alessandra; Kowalczyk, Katarzyna; Rakownikow Jersie-Christensen, Rosa; Bertalot, Giovanni; Confalonieri, Stefano; Brunak, Søren; Jensen, Lars J; Cavallaro, Ugo; Olsen, Jesper V

2017-03-28

Our understanding of the molecular determinants of cancer is still inadequate because of cancer heterogeneity. Here, using epithelial ovarian cancer (EOC) as a model system, we analyzed a minute amount of patient-derived epithelial cells from either healthy or cancerous tissues by single-shot mass-spectrometry-based phosphoproteomics. Using a multi-disciplinary approach, we demonstrated that primary cells recapitulate tissue complexity and represent a valuable source of differentially expressed proteins and phosphorylation sites that discriminate cancer from healthy cells. Furthermore, we uncovered kinase signatures associated with EOC. In particular, CDK7 targets were characterized in both EOC primary cells and ovarian cancer cell lines. We showed that CDK7 controls cell proliferation and that pharmacological inhibition of CDK7 selectively represses EOC cell proliferation. Our approach defines the molecular landscape of EOC, paving the way for efficient therapeutic approaches for patients. Finally, we highlight the potential of phosphoproteomics to identify clinically relevant and druggable pathways in cancer. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Measuring multivariate association and beyond

PubMed Central

Josse, Julie; Holmes, Susan

2017-01-01

Simple correlation coefficients between two variables have been generalized to measure association between two matrices in many ways. Coefficients such as the RV coefficient, the distance covariance (dCov) coefficient and kernel based coefficients are being used by different research communities. Scientists use these coefficients to test whether two random vectors are linked. Once it has been ascertained that there is such association through testing, then a next step, often ignored, is to explore and uncover the association’s underlying patterns. This article provides a survey of various measures of dependence between random vectors and tests of independence and emphasizes the connections and differences between the various approaches. After providing definitions of the coefficients and associated tests, we present the recent improvements that enhance their statistical properties and ease of interpretation. We summarize multi-table approaches and provide scenarii where the indices can provide useful summaries of heterogeneous multi-block data. We illustrate these different strategies on several examples of real data and suggest directions for future research. PMID:29081877

Genomic Epidemiology Reconstructs the Introduction and Spread of Zika Virus in Central America and Mexico.

PubMed

Thézé, Julien; Li, Tony; du Plessis, Louis; Bouquet, Jerome; Kraemer, Moritz U G; Somasekar, Sneha; Yu, Guixia; de Cesare, Mariateresa; Balmaseda, Angel; Kuan, Guillermina; Harris, Eva; Wu, Chieh-Hsi; Ansari, M Azim; Bowden, Rory; Faria, Nuno R; Yagi, Shigeo; Messenger, Sharon; Brooks, Trevor; Stone, Mars; Bloch, Evan M; Busch, Michael; Muñoz-Medina, José E; González-Bonilla, Cesar R; Wolinsky, Steven; López, Susana; Arias, Carlos F; Bonsall, David; Chiu, Charles Y; Pybus, Oliver G

2018-06-13

The Zika virus (ZIKV) epidemic in the Americas established ZIKV as a major public health threat and uncovered its association with severe diseases, including microcephaly. However, genetic epidemiology in some at-risk regions, particularly Central America and Mexico, remains limited. We report 61 ZIKV genomes from this region, generated using metagenomic sequencing with ZIKV-specific enrichment, and combine phylogenetic, epidemiological, and environmental data to reconstruct ZIKV transmission. These analyses revealed multiple independent ZIKV introductions to Central America and Mexico. One introduction, likely from Brazil via Honduras, led to most infections and the undetected spread of ZIKV through the region from late 2014. Multiple lines of evidence indicate biannual peaks of ZIKV transmission in the region, likely driven by varying local environmental conditions for mosquito vectors and herd immunity. The spatial and temporal heterogeneity of ZIKV transmission in Central America and Mexico challenges arbovirus surveillance and disease control measures. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Long-distance communication by specialized cellular projections during pigment pattern development and evolution

PubMed Central

Eom, Dae Seok; Bain, Emily J; Patterson, Larissa B; Grout, Megan E; Parichy, David M

2015-01-01

Changes in gene activity are essential for evolutionary diversification. Yet, elucidating the cellular behaviors that underlie modifications to adult form remains a profound challenge. We use neural crest-derived adult pigmentation of zebrafish and pearl danio to uncover cellular bases for alternative pattern states. We show that stripes in zebrafish require a novel class of thin, fast cellular projection to promote Delta-Notch signaling over long distances from cells of the xanthophore lineage to melanophores. Projections depended on microfilaments and microtubules, exhibited meandering trajectories, and stabilized on target cells to which they delivered membraneous vesicles. By contrast, the uniformly patterned pearl danio lacked such projections, concomitant with Colony stimulating factor 1-dependent changes in xanthophore differentiation that likely curtail signaling available to melanophores. Our study reveals a novel mechanism of cellular communication, roles for differentiation state heterogeneity in pigment cell interactions, and an unanticipated morphogenetic behavior contributing to a striking difference in adult form. DOI: http://dx.doi.org/10.7554/eLife.12401.001 PMID:26701906

Knowledge Discovery in Biological Databases for Revealing Candidate Genes Linked to Complex Phenotypes.

PubMed

Hassani-Pak, Keywan; Rawlings, Christopher

2017-06-13

Genetics and "omics" studies designed to uncover genotype to phenotype relationships often identify large numbers of potential candidate genes, among which the causal genes are hidden. Scientists generally lack the time and technical expertise to review all relevant information available from the literature, from key model species and from a potentially wide range of related biological databases in a variety of data formats with variable quality and coverage. Computational tools are needed for the integration and evaluation of heterogeneous information in order to prioritise candidate genes and components of interaction networks that, if perturbed through potential interventions, have a positive impact on the biological outcome in the whole organism without producing negative side effects. Here we review several bioinformatics tools and databases that play an important role in biological knowledge discovery and candidate gene prioritization. We conclude with several key challenges that need to be addressed in order to facilitate biological knowledge discovery in the future.

Genetic architecture of retinal and macular degenerative diseases: the promise and challenges of next-generation sequencing

PubMed Central

2013-01-01

Inherited retinal degenerative diseases (RDDs) display wide variation in their mode of inheritance, underlying genetic defects, age of onset, and phenotypic severity. Molecular mechanisms have not been delineated for many retinal diseases, and treatment options are limited. In most instances, genotype-phenotype correlations have not been elucidated because of extensive clinical and genetic heterogeneity. Next-generation sequencing (NGS) methods, including exome, genome, transcriptome and epigenome sequencing, provide novel avenues towards achieving comprehensive understanding of the genetic architecture of RDDs. Whole-exome sequencing (WES) has already revealed several new RDD genes, whereas RNA-Seq and ChIP-Seq analyses are expected to uncover novel aspects of gene regulation and biological networks that are involved in retinal development, aging and disease. In this review, we focus on the genetic characterization of retinal and macular degeneration using NGS technology and discuss the basic framework for further investigations. We also examine the challenges of NGS application in clinical diagnosis and management. PMID:24112618

Preparation and Structural Studies on Hybrid Core-Shell Nanoparticles Consisting of Silica Core and Conjugated Block Copolymer Shell Prepared by Surface-Initiated Polymerization

NASA Astrophysics Data System (ADS)

Chatterjee, Sourav; Karam, Tony; Rosu, Cornelia; Li, Xin; Do, Changwoo; Youm, Sang Gil; Haber, Louis; Russo, Paul; Nesterov, Evgueni

Controlled Kumada catalyst-transfer polymerization occurring by chain-growth mechanism was developed for the synthesis of conjugated polymers and block copolymers from the surface of inorganic substrates such as silica nanoparticles. Although synthesis of conjugated polymers via Kumada polymerization became an established method for solution polymerization, carrying out the same reaction in heterogeneous conditions to form monodisperse polymer chains still remains a challenge. We developed and described a simple and efficient approach to the preparation of surface-immobilized layer of catalytic Ni(II) initiator, and demonstrated using it to prepare polymers and block copolymers on silica nanoparticle. The structure of the resulting hybrid nanostructures was thoroughly studied using small-angle neutron and X-ray scattering, thermal analysis, and optical spectroscopy. The photoexcitation energy transfer processes in the conjugated polymer shell were studied via steady-state and time resolved transient absorption spectroscopy. This study uncovered important details of the energy transfer, which will be discussed in this presentation.

Temporal asymmetries in Interbank Market: an empirically grounded Agent-Based Model

NASA Astrophysics Data System (ADS)

Zlatic, Vinko; Popovic, Marko; Abraham, Hrvoje; Caldarelli, Guido; Iori, Giulia

2014-03-01

We analyse the changes in the topology of the structure of the E-mid interbank market in the period from September 1st 1999 to September 1st 2009. We uncover a type of temporal irreversibility in the growth of the largest component of the interbank trading network, which is not common to any of the usual network growth models. Such asymmetry, which is also detected on the growth of the clustering and reciprocity coefficient, reveals that the trading mechanism is driven by different dynamics at the beginning and at the end of the day. We are able to recover the complexity of the system by means of a simple Agent Based Model in which the probability of matching between counter parties depends on a time varying vertex fitness (or attractiveness) describing banks liquidity needs. We show that temporal irreversibility is associated with heterogeneity in the banking system and emerges when the distribution of liquidity shocks across banks is broad. We acknowledge support from FET project FOC-II.

Light Like a Feather: A Fibrous Natural Composite with a Shape Changing from Round to Square.

PubMed

Wang, Bin; Meyers, Marc André

2017-03-01

Only seldom are square/rectangular shapes found in nature. One notable exception is the bird feather rachis, which raises the question: why is the proximal base round but the distal end square? Herein, it is uncovered that, given the same area, square cross sections show higher bending rigidity and are superior in maintaining the original shape, whereas circular sections ovalize upon flexing. This circular-to-square shape change increases the ability of the flight feathers to resist flexure while minimizes the weight along the shaft length. The walls are themselves a heterogeneous composite with the fiber arrangements adjusted to the local stress requirements: the dorsal and ventral regions are composed of longitudinal and circumferential fibers, while lateral walls consist of crossed fibers. This natural avian design is ready to be reproduced, and it is anticipated that the knowledge gained from this work will inspire new materials and structures for, e.g., manned/unmanned aerial vehicles.

Insights into the structure–photoreactivity relationships in well-defined perovskite ferroelectric KNbO 3 nanowires

DOE PAGES

Zhang, Tingting; Lei, Wanying; Liu, Ping; ...

2015-04-23

Structure–function correlations are a central theme in heterogeneous (photo)catalysis. In this study, the geometric and electronic structure of perovskite ferroelectric KNbO 3 nanowires with respective orthorhombic and monoclinic polymorphs have been systematically addressed. By virtue of aberration-corrected scanning transmission electron microscopy, we directly visualize surface photocatalytic active sites, measure local atomic displacements at an accuracy of several picometers, and quantify ferroelectric polarization combined with first-principles calculations. The photoreactivity of the as-prepared KNbO 3 nanowires is assessed toward aqueous rhodamine B degradation under UV light. A synergy between the ferroelectric polarization and electronic structure in photoreactivity enhancement is uncovered, which accountsmore » for the prominent reactivity order: orthorhombic > monoclinic. Additionally, by identifying new photocatalytic products, rhodamine B degradation pathways involving N-deethylation and conjugated structure cleavage are proposed. The findings not only provide new insights into the structure–photoreactivity relationships in perovskite ferroelectric photocatalysts, but also have broad implications in perovskite-based water splitting and photovoltaics, among others.« less

Ciliates in chalk-stream habitats congregate in biodiversity hot spots.

PubMed

Bradley, Mark W; Esteban, Genoveva F; Finlay, Bland J

2010-09-01

Free-living ciliates are a diverse group of microbial eukaryotes that inhabit aquatic environments. They have a vital role within the 'microbial loop', being consumers of microscopic prey such as bacteria, micro-algae, and flagellates, and representing a link between the microscopic and macroscopic components of aquatic food webs. This investigation describes the ciliate communities of four habitats located in the catchment of the River Frome, the major chalk-stream in southern Britain. The ciliate communities were characterised in terms of community assemblage, species abundance and size classes. The ciliate communities investigated proved to be highly diverse, yielding a total of 114 active species. An additional 15 'cryptic' ciliate species were also uncovered. Heterogeneity in the ciliate communities was evident at multiple spatial scales, revealing hot spots of species richness, both within and between habitats. The ciliate communities of habitats with flowing water were composed of smaller ciliates compared to the still-water habitats examined. Copyright 2010 Elsevier Masson SAS. All rights reserved.

Light Like a Feather: A Fibrous Natural Composite with a Shape Changing from Round to Square

PubMed Central

Wang, Bin

2016-01-01

Only seldom are square/rectangular shapes found in nature. One notable exception is the bird feather rachis, which raises the question: why is the proximal base round but the distal end square? Herein, it is uncovered that, given the same area, square cross sections show higher bending rigidity and are superior in maintaining the original shape, whereas circular sections ovalize upon flexing. This circular‐to‐square shape change increases the ability of the flight feathers to resist flexure while minimizes the weight along the shaft length. The walls are themselves a heterogeneous composite with the fiber arrangements adjusted to the local stress requirements: the dorsal and ventral regions are composed of longitudinal and circumferential fibers, while lateral walls consist of crossed fibers. This natural avian design is ready to be reproduced, and it is anticipated that the knowledge gained from this work will inspire new materials and structures for, e.g., manned/unmanned aerial vehicles. PMID:28331789

Distributional Analysis in Educational Evaluation: A Case Study from the New York City Voucher Program

PubMed Central

Domina, Thurston; Penner, Emily; Hoynes, Hilary

2014-01-01

We use quantile treatment effects estimation to examine the consequences of the random-assignment New York City School Choice Scholarship Program (NYCSCSP) across the distribution of student achievement. Our analyses suggest that the program had negligible and statistically insignificant effects across the skill distribution. In addition to contributing to the literature on school choice, the paper illustrates several ways in which distributional effects estimation can enrich educational research: First, we demonstrate that moving beyond a focus on mean effects estimation makes it possible to generate and test new hypotheses about the heterogeneity of educational treatment effects that speak to the justification for many interventions. Second, we demonstrate that distributional effects can uncover issues even with well-studied datasets by forcing analysts to view their data in new ways. Finally, such estimates highlight where in the overall national achievement distribution test scores of children exposed to particular interventions lie; this is important for exploring the external validity of the intervention’s effects. PMID:26207158

Integrating Insults: Using Fault Tree Analysis to Guide Schizophrenia Research across Levels of Analysis.

PubMed

MacDonald Iii, Angus W; Zick, Jennifer L; Chafee, Matthew V; Netoff, Theoden I

2015-01-01

The grand challenges of schizophrenia research are linking the causes of the disorder to its symptoms and finding ways to overcome those symptoms. We argue that the field will be unable to address these challenges within psychiatry's standard neo-Kraepelinian (DSM) perspective. At the same time the current corrective, based in molecular genetics and cognitive neuroscience, is also likely to flounder due to its neglect for psychiatry's syndromal structure. We suggest adopting a new approach long used in reliability engineering, which also serves as a synthesis of these approaches. This approach, known as fault tree analysis, can be combined with extant neuroscientific data collection and computational modeling efforts to uncover the causal structures underlying the cognitive and affective failures in people with schizophrenia as well as other complex psychiatric phenomena. By making explicit how causes combine from basic faults to downstream failures, this approach makes affordances for: (1) causes that are neither necessary nor sufficient in and of themselves; (2) within-diagnosis heterogeneity; and (3) between diagnosis co-morbidity.

Generation of Bright, Spatially Coherent Soft X-Ray High Harmonics in a Hollow Waveguide Using Two-Color Synthesized Laser Pulses.

PubMed

Jin, Cheng; Stein, Gregory J; Hong, Kyung-Han; Lin, C D

2015-07-24

We investigate the efficient generation of low-divergence high-order harmonics driven by waveform-optimized laser pulses in a gas-filled hollow waveguide. The drive waveform is obtained by synthesizing two-color laser pulses, optimized such that highest harmonic yields are emitted from each atom. Optimization of the gas pressure and waveguide configuration has enabled us to produce bright and spatially coherent harmonics extending from the extreme ultraviolet to soft x rays. Our study on the interplay among waveguide mode, atomic dispersion, and plasma effect uncovers how dynamic phase matching is accomplished and how an optimized waveform is maintained when optimal waveguide parameters (radius and length) and gas pressure are identified. Our analysis should help laboratory development in the generation of high-flux bright coherent soft x rays as tabletop light sources for applications.

Emergence, evolution and scaling of online social networks.

PubMed

Wang, Le-Zhi; Huang, Zi-Gang; Rong, Zhi-Hai; Wang, Xiao-Fan; Lai, Ying-Cheng

2014-01-01

Online social networks have become increasingly ubiquitous and understanding their structural, dynamical, and scaling properties not only is of fundamental interest but also has a broad range of applications. Such networks can be extremely dynamic, generated almost instantaneously by, for example, breaking-news items. We investigate a common class of online social networks, the user-user retweeting networks, by analyzing the empirical data collected from Sina Weibo (a massive twitter-like microblogging social network in China) with respect to the topic of the 2011 Japan earthquake. We uncover a number of algebraic scaling relations governing the growth and structure of the network and develop a probabilistic model that captures the basic dynamical features of the system. The model is capable of reproducing all the empirical results. Our analysis not only reveals the basic mechanisms underlying the dynamics of the retweeting networks, but also provides general insights into the control of information spreading on such networks.

Sequential detection of temporal communities by estrangement confinement.

PubMed

Kawadia, Vikas; Sreenivasan, Sameet

2012-01-01

Temporal communities are the result of a consistent partitioning of nodes across multiple snapshots of an evolving network, and they provide insights into how dense clusters in a network emerge, combine, split and decay over time. To reliably detect temporal communities we need to not only find a good community partition in a given snapshot but also ensure that it bears some similarity to the partition(s) found in the previous snapshot(s), a particularly difficult task given the extreme sensitivity of community structure yielded by current methods to changes in the network structure. Here, motivated by the inertia of inter-node relationships, we present a new measure of partition distance called estrangement, and show that constraining estrangement enables one to find meaningful temporal communities at various degrees of temporal smoothness in diverse real-world datasets. Estrangement confinement thus provides a principled approach to uncovering temporal communities in evolving networks.

SETI - A preliminary search for narrowband signals at microwave frequencies

NASA Technical Reports Server (NTRS)

Cuzzi, J. N.; Clark, T. A.; Tarter, J. C.; Black, D. C.

1977-01-01

In the search for intelligent signals of extraterrestrial origin, certain forms of signals merit immediate and special attention. Extremely narrowband signals of spectral width similar to our own television transmissions are most favored energetically and least likely to be confused with natural celestial emission. A search of selected stars has been initiated using observational and data processing techniques optimized for the detection of such signals. These techniques allow simultaneous observation of 10 to the 5th to 10 to the 6th channels within the observed spectral range. About two hundred nearby (within 80 LY) solar type stars have been observed at frequencies near the main microwave transitions of the hydroxyl radical. In addition, several molecular (hydroxyl) masers and other non-thermal sources have been observed in this way in order to uncover any possible fine spectral structure of natural origin and to investigate the potential of such an instrument for radioastronomy.

Global analysis of A-to-I RNA editing reveals association with common disease variants

PubMed Central

Jain, Rajeev; Jain, Anamika; Betsholtz, Christer; Giannarelli, Chiara; Kovacic, Jason C.; Ruusalepp, Arno; Skogsberg, Josefin; Hao, Ke; Schadt, Eric E.

2018-01-01

RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process. PMID:29527417

Dissipative Effects on Inertial-Range Statistics at High Reynolds Numbers.

PubMed

Sinhuber, Michael; Bewley, Gregory P; Bodenschatz, Eberhard

2017-09-29

Using the unique capabilities of the Variable Density Turbulence Tunnel at the Max Planck Institute for Dynamics and Self-Organization, Göttingen, we report experimental measurements in classical grid turbulence that uncover oscillations of the velocity structure functions in the inertial range. This was made possible by measuring extremely long time series of up to 10^{10} samples of the turbulent fluctuating velocity, which corresponds to O(10^{7}) integral length scales. The measurements were conducted in a well-controlled environment at a wide range of high Reynolds numbers from R_{λ}=110 up to R_{λ}=1600, using both traditional hot-wire probes as well as the nanoscale thermal anemometry probe developed at Princeton University. An implication of the observed oscillations is that dissipation influences the inertial-range statistics of turbulent flows at scales significantly larger than predicted by current models and theories.

KSC-08pd2647

NASA Image and Video Library

2008-09-18

CAPE CANAVERAL, Fla. - In the Payload Hazardous Servicing Facility at NASA's Kennedy Space Center, the Super Lightweight Interchangeable Carrier, or SLIC, is uncovered so that technicians can clean contaminants found earlier. Contamination discovered Sept. 17 during preparations to deliver NASA's Hubble Space Telescope servicing payload to Launch Pad 39A will be removed. Cleanliness is extremely important for space shuttle Atlantis’ STS-125 mission to Hubble, and the teams have insured that the SLIC is ready to fly. The SLIC, which holds battery module assemblies, is built with state-of-the-art, lightweight, composite materials - carbon fiber with a cyanate ester resin and a titanium metal matrix composite. These composites have greater strength-to-mass ratios than the metals typically used in spacecraft design. The carrier is one of four being transferred to Launch Pad 39A. At the pad, the carriers will be loaded into Atlantis’ payload bay. Launch of Atlantis is targeted for Oct. 10. Photo credit: NASA/Jack Pfaller

Self-amplified photo-induced gap quenching in a correlated electron material

PubMed Central

Mathias, S.; Eich, S.; Urbancic, J.; Michael, S.; Carr, A. V.; Emmerich, S.; Stange, A.; Popmintchev, T.; Rohwer, T.; Wiesenmayer, M.; Ruffing, A.; Jakobs, S.; Hellmann, S.; Matyba, P.; Chen, C.; Kipp, L.; Bauer, M.; Kapteyn, H. C.; Schneider, H. C.; Rossnagel, K.; Murnane, M. M.; Aeschlimann, M.

2016-01-01

Capturing the dynamic electronic band structure of a correlated material presents a powerful capability for uncovering the complex couplings between the electronic and structural degrees of freedom. When combined with ultrafast laser excitation, new phases of matter can result, since far-from-equilibrium excited states are instantaneously populated. Here, we elucidate a general relation between ultrafast non-equilibrium electron dynamics and the size of the characteristic energy gap in a correlated electron material. We show that carrier multiplication via impact ionization can be one of the most important processes in a gapped material, and that the speed of carrier multiplication critically depends on the size of the energy gap. In the case of the charge-density wave material 1T-TiSe2, our data indicate that carrier multiplication and gap dynamics mutually amplify each other, which explains—on a microscopic level—the extremely fast response of this material to ultrafast optical excitation. PMID:27698341

Self-folding origami at any energy scale

NASA Astrophysics Data System (ADS)

Pinson, Matthew B.; Stern, Menachem; Carruthers Ferrero, Alexandra; Witten, Thomas A.; Chen, Elizabeth; Murugan, Arvind

2017-05-01

Programmable stiff sheets with a single low-energy folding motion have been sought in fields ranging from the ancient art of origami to modern meta-materials research. Despite such attention, only two extreme classes of crease patterns are usually studied; special Miura-Ori-based zero-energy patterns, in which crease folding requires no sheet bending, and random patterns with high-energy folding, in which the sheet bends as much as creases fold. We present a physical approach that allows systematic exploration of the entire space of crease patterns as a function of the folding energy. Consequently, we uncover statistical results in origami, finding the entropy of crease patterns of given folding energy. Notably, we identify three classes of Mountain-Valley choices that have widely varying `typical' folding energies. Our work opens up a wealth of experimentally relevant self-folding origami designs not reliant on Miura-Ori, the Kawasaki condition or any special symmetry in space.

Molecular diversity of toxic components from the scorpion Heterometrus petersii venom revealed by proteomic and transcriptome analysis.

PubMed

Ma, Yibao; Zhao, Yong; Zhao, Ruiming; Zhang, Weiping; He, Yawen; Wu, Yingliang; Cao, Zhijian; Guo, Lin; Li, Wenxin

2010-07-01

Scorpion venoms contain a vast untapped reservoir of natural products, which have the potential for medicinal value in drug discovery. In this study, toxin components from the scorpion Heterometrus petersii venom were evaluated by transcriptome and proteome analysis.Ten known families of venom peptides and proteins were identified, which include: two families of potassium channel toxins, four families of antimicrobial and cytolytic peptides,and one family from each of the calcium channel toxins, La1-like peptides, phospholipase A2,and the serine proteases. In addition, we also identified 12 atypical families, which include the acid phosphatases, diuretic peptides, and ten orphan families. From the data presented here, the extreme diversity and convergence of toxic components in scorpion venom was uncovered. Our work demonstrates the power of combining transcriptomic and proteomic approaches in the study of animal venoms.

KSC-2012-3813

NASA Image and Video Library

2012-07-13

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians use a lift to uncover and inspect the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3812

NASA Image and Video Library

2012-07-13

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians use a lift to uncover and inspect the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket.rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3814

NASA Image and Video Library

2012-07-13

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians use a lift to uncover and inspect the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

KSC-2012-3807

NASA Image and Video Library

2012-07-13

CAPE CANAVERAL, Fla. - Inside the Astrotech payload processing facility near NASA’s Kennedy Space Center in Florida, technicians use a lift to inspect and uncover the nose cone fairing for the Radiation Belt Storm Probes, or RBSP, spacecraft. The nose faring will house and protect the RBSP during liftoff aboard an Atlas V rocket. NASA’s RBSP mission will help us understand the sun’s influence on Earth and near-Earth space by studying the Earth’s radiation belts on various scales of space and time. RBSP will begin its mission of exploration of Earth’s Van Allen radiation belts and the extremes of space weather after its liftoff aboard a United Launch Alliance Atlas V from Space Launch Complex 41 at Cape Canaveral Air Force Station, Fla. Liftoff is targeted for Aug. 23, 2012. For more information, visit http://www.nasa.gov/rbsp. Photo credit: NASA/Charisse Nahser

Coupling the Leidenfrost effect and elastic deformations to power sustained bouncing

NASA Astrophysics Data System (ADS)

Waitukaitis, Scott R.; Zuiderwijk, Antal; Souslov, Anton; Coulais, Corentin; van Hecke, Martin

2017-11-01

The Leidenfrost effect occurs when an object near a hot surface vaporizes rapidly enough to lift itself up and hover. Although well understood for liquids and stiff sublimable solids, nothing is known about the effect with materials whose stiffness lies between these extremes. Here we introduce a new phenomenon that occurs with vaporizable soft solids--the elastic Leidenfrost effect. By dropping hydrogel spheres onto hot surfaces we find that, rather than hovering, they energetically bounce several times their diameter for minutes at a time. With high-speed video during a single impact, we uncover high-frequency microscopic gap dynamics at the sphere/substrate interface. We show how these otherwise-hidden agitations constitute work cycles that harvest mechanical energy from the vapour and sustain the bouncing. Our findings suggest a new strategy for injecting mechanical energy into a widely used class of soft materials, with potential relevance to fields such as active matter, soft robotics and microfluidics.

Standing variation in spatially growing populations

NASA Astrophysics Data System (ADS)

Fusco, Diana; Gralka, Matti; Kayser, Jona; Hallatschek, Oskar

Patterns of genetic diversity not only reflect the evolutionary history of a species but they can also determine the evolutionary response to environmental change. For instance, the standing genetic diversity of a microbial population can be key to rescue in the face of an antibiotic attack. While genetic diversity is in general shaped by both demography and evolution, very little is understood when both factors matter, as e.g. for biofilms with pronounced spatial organization. Here, we quantitatively explore patterns of genetic diversity by using microbial colonies and well-mixed test tube populations as antipodal model systems with extreme and very little spatial structure, respectively. We find that Eden model simulations and KPZ theory can remarkably reproduce the genetic diversity in microbial colonies obtained via population sequencing. The excellent agreement allows to draw conclusions on the resilience of spatially-organized populations and to uncover new strategies to contain antibiotic resistance.

MERINOVA: Meteorological risks as drivers of environmental innovation in agro-ecosystem management

NASA Astrophysics Data System (ADS)

Gobin, Anne; Oger, Robert; Marlier, Catherine; Van De Vijver, Hans; Vandermeulen, Valerie; Van Huylenbroeck, Guido; Zamani, Sepideh; Curnel, Yannick; Mettepenningen, Evi

2013-04-01

The BELSPO funded project 'MERINOVA' deals with risks associated with extreme weather phenomena and with risks of biological origin such as pests and diseases. The major objectives of the proposed project are to characterise extreme meteorological events, assess the impact on Belgian agro-ecosystems, characterise their vulnerability and resilience to these events, and explore innovative adaptation options to agricultural risk management. The project comprises of five major parts that reflect the chain of risks: (i) Hazard: Assessing the likely frequency and magnitude of extreme meteorological events by means of probability density functions; (ii) Impact: Analysing the potential bio-physical and socio-economic impact of extreme weather events on agro-ecosystems in Belgium using process-based modelling techniques commensurate with the regional scale; (iii) Vulnerability: Identifying the most vulnerable agro-ecosystems using fuzzy multi-criteria and spatial analysis; (iv) Risk Management: Uncovering innovative risk management and adaptation options using actor-network theory and fuzzy cognitive mapping techniques; and, (v) Communication: Communicating to research, policy and practitioner communities using web-based techniques. The different tasks of the MERINOVA project require expertise in several scientific disciplines: meteorology, statistics, spatial database management, agronomy, bio-physical impact modelling, socio-economic modelling, actor-network theory, fuzzy cognitive mapping techniques. These expertises are shared by the four scientific partners who each lead one work package. The MERINOVA project will concentrate on promoting a robust and flexible framework by demonstrating its performance across Belgian agro-ecosystems, and by ensuring its relevance to policy makers and practitioners. Impacts developed from physically based models will not only provide information on the state of the damage at any given time, but also assist in understanding the links between different factors causing damage and determining bio-physical vulnerability. Socio-economic impacts will enlarge the basis for vulnerability mapping, risk management and adaptation options. A strong expert and end-user network will be established to help disseminating and exploiting project results to meet user needs.

Molecular diagnostics for hereditary hearing loss in children.

PubMed

Sommen, Manou; Wuyts, Wim; Van Camp, Guy

2017-08-01

Hearing loss (HL) is the most common birth defect in industrialized countries with far-reaching social, psychological and cognitive implications. It is an extremely heterogeneous disease, complicating molecular testing. The introduction of next-generation sequencing (NGS) has resulted in great progress in diagnostics allowing to study all known HL genes in a single assay. The diagnostic yield is currently still limited, but has the potential to increase substantially. Areas covered: In this review the utility of NGS and the problems for comprehensive molecular testing for HL are evaluated and discussed. Expert commentary: Different publications have proven the appropriateness of NGS for molecular testing of heterogeneous diseases such as HL. However, several problems still exist, such as pseudogenic background of some genes and problematic copy number variant analysis on targeted NGS data. Another main challenge for the future will be the establishment of population specific mutation-spectra to achieve accurate personalized comprehensive molecular testing for HL.

Micro-view-cell for phase behaviour and in situ Raman analysis of heterogeneously catalysed CO2 hydrogenation

NASA Astrophysics Data System (ADS)

Reymond, Helena; Rudolf von Rohr, Philipp

2017-11-01

The operando study of CO2 hydrogenation is fundamental for a more rational optimisation of heterogeneous catalyst and reactor designs. To further complement the established efficiency of microreactors in reaction screening and bridge the operating and optical gaps, a micro-view-cell is presented for Raman microscopy at extreme conditions with minimum flow interference for genuine reaction analysis. Based on a flat sapphire window unit sealed in a plug flow-type enclosure holding the sample, the cell features unique 14 mm working distance and 0.36 numerical aperture and resists 400 °C and 500 bars. The use of the cell as an in situ tool for fast process monitoring and surface catalyst characterisation is demonstrated with phase behaviour and chemical analysis of the methanol synthesis over a commercial Cu/ZnO/Al2O3 catalyst.

ZnO nanoparticles as an efficient, heterogeneous, reusable, and ecofriendly catalyst for four-component one-pot green synthesis of pyranopyrazole derivatives in water.

PubMed

Sachdeva, Harshita; Saroj, Rekha

2013-01-01

An extremely efficient catalytic protocol for the synthesis of a series of pyranopyrazole derivatives developed in a one-pot four-component approach in the presence of ZnO nanoparticles as heterogeneous catalyst using water as a green solvent is reported. Greenness of the process is well instituted as water is exploited both as reaction media and medium for synthesis of catalyst. The ZnO nanoparticles exhibited excellent catalytic activity, and the proposed methodology is capable of providing the desired products in good yield (85-90%) and short reaction time. After reaction course, ZnO nanoparticles can be recycled and reused without any apparent loss of activity which makes this process cost effective and hence ecofriendly. All the synthesized compounds have been characterized on the basis of elemental analysis, IR, ¹H NMR, and ¹³C NMR spectral studies.

Sequence of a second gene encoding bovine submaxillary mucin: implication for mucin heterogeneity and cloning.

PubMed

Jiang, W; Woitach, J T; Gupta, D; Bhavanandan, V P

1998-10-20

Secreted epithelial mucins are extremely large and heterogeneous glycoproteins. We report the 5 kilobase DNA sequence of a second gene, BSM2, which encodes bovine submaxillary mucin. The determined nucleotide and deduced amino acid sequences of BSM2 are 95.2% and 92. 2% identical, respectively, to those of the previously described BSM1 gene isolated from the same cow. Further, the five predicted protein domains of the two genes are 100%, 94%, 93%, 77%, and 88% identical. Based on the above results, we propose that expression of multiple homologous core proteins from a single animal is a factor in generating diversity of saccharides in mucins and in providing resistance of the molecules to proteolysis. In addition, this work raises several important issues in mucin cloning such as assembling sequences from seemingly overlapping clones and deducing consensus sequences for nearly identical tandem repeats. Copyright 1998 Academic Press.

Anomalous and non-Gaussian diffusion in Hertzian spheres

NASA Astrophysics Data System (ADS)

Ouyang, Wenze; Sun, Bin; Sun, Zhiwei; Xu, Shenghua

2018-09-01

By means of molecular dynamics simulations, we study the non-Gaussian diffusion in the fluid of Hertzian spheres. The time dependent non-Gaussian parameter, as an indicator of the dynamic heterogeneity, is increased with the increasing of temperature. When the temperature is high enough, the dynamic heterogeneity becomes very significant, and it seems counterintuitive that the maximum of non-Gaussian parameter and the position of its peak decrease monotonically with the increasing of density. By fitting the curves of self intermediate scattering function, we find that the character relaxation time τα is surprisingly not coupled with the time τmax where the non-Gaussian parameter reaches to a maximum. The intriguing features of non-Gaussian diffusion at high enough temperatures can be associated with the weakly correlated mean-field behavior of Hertzian spheres. Especially the time τmax is nearly inversely proportional to the density at extremely high temperatures.

Physical limits to biomechanical sensing in disordered fibre networks

NASA Astrophysics Data System (ADS)

Beroz, Farzan; Jawerth, Louise M.; Münster, Stefan; Weitz, David A.; Broedersz, Chase P.; Wingreen, Ned S.

2017-07-01

Cells actively probe and respond to the stiffness of their surroundings. Since mechanosensory cells in connective tissue are surrounded by a disordered network of biopolymers, their in vivo mechanical environment can be extremely heterogeneous. Here we investigate how this heterogeneity impacts mechanosensing by modelling the cell as an idealized local stiffness sensor inside a disordered fibre network. For all types of networks we study, including experimentally-imaged collagen and fibrin architectures, we find that measurements applied at different points yield a strikingly broad range of local stiffnesses, spanning roughly two decades. We verify via simulations and scaling arguments that this broad range of local stiffnesses is a generic property of disordered fibre networks. Finally, we show that to obtain optimal, reliable estimates of global tissue stiffness, a cell must adjust its size, shape, and position to integrate multiple stiffness measurements over extended regions of space.

The rifted margin of Saudi Arabia

NASA Astrophysics Data System (ADS)

McClain, J. S.; Orcutt, J. A.

The structure of rifted continental margins has always been of great scientific interest, and now, with dwindling economic oil deposits, these complex geological features assume practical importance as well. The ocean-continent transition is, by definition, laterally heterogeneous and likely to be extremely complicated. The southernmost shotpoints (4, 5, and 6) in the U.S. Geological Survey seismic refraction profile in the Kingdom of Saudi Arabia lie within a transition region and thus provide a testing ground for methods that treat wave propagation in laterally heterogeneous media. This portion of the profile runs from the Farasan Islands in the Red Sea across the coast line and the Hijaz-Asir escarpment into the Hijaz-Asir tectonic province. Because the southernmost shotpoint is within the margin of the Saudi sub-continent, the full transition region is not sampled. Furthermore, such an experiment is precluded by the narrowness of the purely oceanic portion of the Red Sea.

Repeatability and reproducibility of intracellular molar concentration assessed by synchrotron-based x-ray fluorescence microscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Merolle, L., E-mail: lucia.merolle@elettra.eu; Gianoncelli, A.; Malucelli, E., E-mail: emil.malucelli@unibo.it

2016-01-28

Elemental analysis of biological sample can give information about content and distribution of elements essential for human life or trace elements whose absence is the cause of abnormal biological function or development. However, biological systems contain an ensemble of cells with heterogeneous chemistry and elemental content; therefore, accurate characterization of samples with high cellular heterogeneity may only be achieved by analyzing single cells. Powerful methods in molecular biology are abundant, among them X-Ray microscopy based on synchrotron light source has gaining increasing attention thanks to its extremely sensitivity. However, reproducibility and repeatability of these measurements is one of the majormore » obstacles in achieving a statistical significance in single cells population analysis. In this study, we compared the elemental content of human colon adenocarcinoma cells obtained by three distinct accesses to synchrotron radiation light.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luszczek, Piotr R; Tomov, Stanimire Z; Dongarra, Jack J

We present an efficient and scalable programming model for the development of linear algebra in heterogeneous multi-coprocessor environments. The model incorporates some of the current best design and implementation practices for the heterogeneous acceleration of dense linear algebra (DLA). Examples are given as the basis for solving linear systems' algorithms - the LU, QR, and Cholesky factorizations. To generate the extreme level of parallelism needed for the efficient use of coprocessors, algorithms of interest are redesigned and then split into well-chosen computational tasks. The tasks execution is scheduled over the computational components of a hybrid system of multi-core CPUs andmore » coprocessors using a light-weight runtime system. The use of lightweight runtime systems keeps scheduling overhead low, while enabling the expression of parallelism through otherwise sequential code. This simplifies the development efforts and allows the exploration of the unique strengths of the various hardware components.« less

Astrocytic Disruption in Traumatic Brain Injury and Alzheimer’s Disease

DTIC Science & Technology

2014-10-01

appropriate age range and pressure to use. A major challenge has been the genetic heterogeneity of the 5xFAD mice that were generated and maintained on a...mixed C57BL/6J and SJL/J background. As hemizygous 5xFAD mice carrying the AD related allele with unknown genetic background were backcrossed with...imaging from astrocytes will be extremely feasible using a genetic approach in the future once the C57 congenic 5xFAD line is established. Aim 3 - To

Computational analysis of electrokinetically driven flow mixing in microchannels with patterned blocks

NASA Astrophysics Data System (ADS)

Chang, C.-C.; Yang, R.-J.

2004-04-01

Electroosmotic flow in microchannels is restricted to low Reynolds number regimes characterized by extremely weak inertia forces and laminar flow. Consequently, the mixing of different species occurs primarily through diffusion, and hence cannot readily be achieved within a short mixing channel. The current study presents a numerical investigation of electrokinetically driven flow mixing in microchannels with various numbers of incorporated patterned rectangular blocks. Furthermore, a novel approach is introduced which patterns heterogeneous surfaces on the upper faces of these rectangular blocks in order to enhance species mixing. The simulation results confirm that the introduction of rectangular blocks within the mixing channel slightly enhances species mixing by constricting the bulk flow, hence creating a stronger diffusion effect. However, it is noted that a large number of blocks and hence a long mixing channel are required if a complete mixing of the species is to be obtained. The results also indicate that patterning heterogeneous upper surfaces on the rectangular blocks is an effective means of enhancing the species mixing. It is shown that increasing the magnitude of the heterogeneous surface zeta potential enables a reduction in the mixing channel length and an improved degree of mixing efficiency.

Establishment and Characterization of a Highly Tumourigenic and Cancer Stem Cell Enriched Pancreatic Cancer Cell Line as a Well Defined Model System

PubMed Central

Fredebohm, Johannes; Boettcher, Michael; Eisen, Christian; Gaida, Matthias M.; Heller, Anette; Keleg, Shereen; Tost, Jörg; Greulich-Bode, Karin M.; Hotz-Wagenblatt, Agnes; Lathrop, Mark; Giese, Nathalia A.; Hoheisel, Jörg D.

2012-01-01

Standard cancer cell lines do not model the intratumoural heterogeneity situation sufficiently. Clonal selection leads to a homogeneous population of cells by genetic drift. Heterogeneity of tumour cells, however, is particularly critical for therapeutically relevant studies, since it is a prerequisite for acquiring drug resistance and reoccurrence of tumours. Here, we report the isolation of a highly tumourigenic primary pancreatic cancer cell line, called JoPaca-1 and its detailed characterization at multiple levels. Implantation of as few as 100 JoPaca-1 cells into immunodeficient mice gave rise to tumours that were histologically very similar to the primary tumour. The high heterogeneity of JoPaca-1 was reflected by diverse cell morphology and a substantial number of chromosomal aberrations. Comparative whole-genome sequencing of JoPaca-1 and BxPC-3 revealed mutations in genes frequently altered in pancreatic cancer. Exceptionally high expression of cancer stem cell markers and a high clonogenic potential in vitro and in vivo was observed. All of these attributes make this cell line an extremely valuable model to study the biology of and pharmaceutical effects on pancreatic cancer. PMID:23152778

Thermokinetics of heterogeneous droplet nucleation on conically textured substrates.

PubMed

Singha, Sanat K; Das, Prasanta K; Maiti, Biswajit

2015-11-28

Within the framework of the classical theory of heterogeneous nucleation, a thermokinetic model is developed for line-tension-associated droplet nucleation on conical textures considering growth or shrinkage of the formed cluster due to both interfacial and peripheral monomer exchange and by considering different geometric configurations. Along with the principle of free energy extremization, Katz kinetic approach has been employed to study the effect of substrate conicity and wettability on the thermokinetics of heterogeneous water droplet nucleation. Not only the peripheral tension is found to have a considerable effect on the free energy barrier but also the substrate hydrophobicity and hydrophilicity are observed to switch over their roles between conical crest and trough for different growth rates of the droplet. Besides, the rate of nucleation increases and further promotes nucleation for negative peripheral tension as it diminishes the free energy barrier appreciably. Moreover, nucleation inhibition can be achievable for positive peripheral tension due to the enhancement of the free energy barrier. Analyzing all possible geometric configurations, the hydrophilic narrower conical cavity is found to be the most preferred nucleation site. These findings suggest a physical insight into the context of surface engineering for the promotion or the suppression of nucleation on real or engineered substrates.

Characterisation of the heterogeneity of karst using electrical geophysics - applications in SW China

NASA Astrophysics Data System (ADS)

Binley, A. M.; Cheng, Q.; Tao, M.; Chen, X.

2017-12-01

The southwest China karst region is one of the largest globally continuous karst areas. The great (structural, hydrological and geochemical) complexity of karstic environments and their rapidly evolving nature make them extremely vulnerable to natural and anthropogenic processes/activities. Characterising the location and properties of structures within the karst critical zone, and understanding how the landform is evolving is essential for the mitigation and adaption to locally- and globally-driven changes. Because of the specific nature of karst geology and geomorphology in the humid tropics and subtropics, spatial heterogeneity is high, evidenced by specific landforms features. Such heterogeneity leads to a high dynamic variability of hydrological processes in space and time, along with a complex exchange of surface water and groundwater. Investigating karst hydrogeological features is extremely challenging because of the three-dimensional nature of the system. Observations from boreholes can vary significantly over several metres, making conventional aquifer investigative methods limited. Geophysical methods have emerged as potentially powerful tools for hydrogeological investigations. Geophysical surveys can help to obtain more insight into the complex conduit networks and depth of weathering, both of which can provide quantitative information about the hydrological and hydrochemical dynamics of the system, in addition to providing a better understanding of how critical zone structures have been established and how the landscape is evolving. We present here results from recent geophysical field campaigns in SW China. We illustrate the effectiveness of electrical methods for mapping soil infil in epikarst and report results from field-based investigations along hillslope and valley transects. Our results reveal distinct zones of relatively high electrical conductivity to depths of tens of metres, which we attribute to localised increased fracture density. We discuss how such surveys can be used alongside other investigative techniques to help improve our understanding of the structure and function of this complex subsurface environment.

Soil water repellency under stones, forest residue mulch and bare soil following wildfire.

NASA Astrophysics Data System (ADS)

Martins, Martinho A. S.; Prats, Sérgio A.; van Keulen, Daan; Vieira, Diana C. S.; Silva, Flávio C.; Keizer, Jan J.; Verheijen, Frank G. A.

2017-04-01

Soil water repellency (SWR) is a physical property that is commonly defined as the aptitude of soil to resist wetting. It has been documented for a wide range of soil and vegetation types, and can vary with soil organic matter (SOM) content and type, soil texture, soil moisture content (SMC) and soil temperature. Fire can induce, enhance or destroy SWR and, therefore, lead to considerable changes in soil water infiltration and storage and increase soil erosion by water, thereby weakening soil quality. In Portugal, wildfires occur frequently and affect large areas, on average some 100000 ha per year, but over 300000 ha in extreme years such as 2003 and 2005. This can have important implications in geomorphological and hydrological processes, as evidenced by the strong and sometimes extreme responses in post-fire runoff and erosion reported from various parts of the world, including Portugal. Thereby, the application of mulches from various materials to cover burned areas has been found to be an efficient stabilization treatment. However, little is known about possible side effects on SWR, especially long term effects. Forest SWR is very heterogeneous, as a result of variation in proximity to trees/shrubs, litter type and thickness, cracks, roots, and stones. This study targeted the spatial heterogeneity of soil water repellency under eucalypt plantation, five years after a wildfire and forest residue mulching application. The main objectives of this work were: 1) to assess the long-term effect of mulching application on the strength and spatial heterogeneity of topsoil SWR, by comparing SWR on bare soil, under stones, and under mulching remains; 2) to assess SWR at 1 cm depth between O and Ah horizons. The soil surface results showed that untreated bare soil areas were slightly more water repellent than mulched areas. However, under stones there were no SWR differences between mulched and control areas. At 1 cm depth, there was a marked mulching effect on SWR, even 5 years after application.

Evaluating of the spatial heterogeneity of soil loss tolerance and its effects on erosion risk in the carbonate areas of southern China

NASA Astrophysics Data System (ADS)

Li, Yue; Bai, Xiao Yong; Jie Wang, Shi; Qin, Luo Yi; Chao Tian, Yi; Jie Luo, Guang

2017-05-01

Soil loss tolerance (T value) is one of the criteria in determining the necessity of erosion control measures and ecological restoration strategy. However, the validity of this criterion in subtropical karst regions is strongly disputed. In this study, T value is calculated based on soil formation rate by using a digital distribution map of carbonate rock assemblage types. Results indicated a spatial heterogeneity and diversity in soil loss tolerance. Instead of only one criterion, a minimum of three criteria should be considered when investigating the carbonate areas of southern China because the one region, one T value concept may not be applicable to this region. T value is proportionate to the amount of argillaceous material, which determines the surface soil thickness of the formations in homogenous carbonate rock areas. Homogenous carbonate rock, carbonate rock intercalated with clastic rock areas and carbonate/clastic rock alternation areas have T values of 20, 50 and 100 t/(km2 a), and they are extremely, severely and moderately sensitive to soil erosion. Karst rocky desertification (KRD) is defined as extreme soil erosion and reflects the risks of erosion. Thus, the relationship between T value and erosion risk is determined using KRD as a parameter. The existence of KRD land is unrelated to the T value, although this parameter indicates erosion sensitivity. Erosion risk is strongly dependent on the relationship between real soil loss (RL) and T value rather than on either erosion intensity or the T value itself. If RL > > T, then the erosion risk is high despite of a low RL. Conversely, if T > > RL, then the soil is safe although RL is high. Overall, these findings may clarify the heterogeneity of T value and its effect on erosion risk in a karst environment.

Interactogeneous: Disease Gene Prioritization Using Heterogeneous Networks and Full Topology Scores

PubMed Central

Gonçalves, Joana P.; Francisco, Alexandre P.; Moreau, Yves; Madeira, Sara C.

2012-01-01

Disease gene prioritization aims to suggest potential implications of genes in disease susceptibility. Often accomplished in a guilt-by-association scheme, promising candidates are sorted according to their relatedness to known disease genes. Network-based methods have been successfully exploiting this concept by capturing the interaction of genes or proteins into a score. Nonetheless, most current approaches yield at least some of the following limitations: (1) networks comprise only curated physical interactions leading to poor genome coverage and density, and bias toward a particular source; (2) scores focus on adjacencies (direct links) or the most direct paths (shortest paths) within a constrained neighborhood around the disease genes, ignoring potentially informative indirect paths; (3) global clustering is widely applied to partition the network in an unsupervised manner, attributing little importance to prior knowledge; (4) confidence weights and their contribution to edge differentiation and ranking reliability are often disregarded. We hypothesize that network-based prioritization related to local clustering on graphs and considering full topology of weighted gene association networks integrating heterogeneous sources should overcome the above challenges. We term such a strategy Interactogeneous. We conducted cross-validation tests to assess the impact of network sources, alternative path inclusion and confidence weights on the prioritization of putative genes for 29 diseases. Heat diffusion ranking proved the best prioritization method overall, increasing the gap to neighborhood and shortest paths scores mostly on single source networks. Heterogeneous associations consistently delivered superior performance over single source data across the majority of methods. Results on the contribution of confidence weights were inconclusive. Finally, the best Interactogeneous strategy, heat diffusion ranking and associations from the STRING database, was used to prioritize genes for Parkinson’s disease. This method effectively recovered known genes and uncovered interesting candidates which could be linked to pathogenic mechanisms of the disease. PMID:23185389

Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity.

PubMed

Dalmasso, Giovanni; Marin Zapata, Paula Andrea; Brady, Nathan Ryan; Hamacher-Brady, Anne

2017-01-01

Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological and mobility dynamics are essential for maintaining mitochondrial functional homeostasis, and alterations both impact and reflect cellular stress states. Mitochondrial homeostasis is further dependent on production (biogenesis) and the removal of damaged mitochondria by selective autophagy (mitophagy). While mitochondrial function, dynamics, biogenesis and mitophagy are highly-integrated processes, it is not fully understood how systemic control in the cell is established to maintain homeostasis, or respond to bioenergetic demands. Here we used agent-based modeling (ABM) to integrate molecular and imaging knowledge sets, and simulate population dynamics of mitochondria and their response to environmental energy demand. Using high-dimensional parameter searches we integrated experimentally-measured rates of mitochondrial biogenesis and mitophagy, and using sensitivity analysis we identified parameter influences on population homeostasis. By studying the dynamics of cellular subpopulations with distinct mitochondrial masses, our approach uncovered system properties of mitochondrial populations: (1) mitochondrial fusion and fission activities rapidly establish mitochondrial sub-population homeostasis, and total cellular levels of mitochondria alter fusion and fission activities and subpopulation distributions; (2) restricting the directionality of mitochondrial mobility does not alter morphology subpopulation distributions, but increases network transmission dynamics; and (3) maintaining mitochondrial mass homeostasis and responding to bioenergetic stress requires the integration of mitochondrial dynamics with the cellular bioenergetic state. Finally, (4) our model suggests sources of, and stress conditions amplifying, cell-to-cell variability of mitochondrial morphology and energetic stress states. Overall, our modeling approach integrates biochemical and imaging knowledge, and presents a novel open-modeling approach to investigate how spatial and temporal mitochondrial dynamics contribute to functional homeostasis, and how subcellular organelle heterogeneity contributes to the emergence of cell heterogeneity.

Chromatin Heterogeneity and Distribution of Regulatory Elements in the Late-Replicating Intercalary Heterochromatin Domains of Drosophila melanogaster Chromosomes

PubMed Central

Khoroshko, Varvara A.; Levitsky, Viktor G.; Zykova, Tatyana Yu.; Antonenko, Oksana V.; Belyaeva, Elena S.; Zhimulev, Igor F.

2016-01-01

Late-replicating domains (intercalary heterochromatin) in the Drosophila genome display a number of features suggesting their organization is quite unique. Typically, they are quite large and encompass clusters of functionally unrelated tissue-specific genes. They correspond to the topologically associating domains and conserved microsynteny blocks. Our study aims at exploring further details of molecular organization of intercalary heterochromatin and has uncovered surprising heterogeneity of chromatin composition in these regions. Using the 4HMM model developed in our group earlier, intercalary heterochromatin regions were found to host chromatin fragments with a particular epigenetic profile. Aquamarine chromatin fragments (spanning 0.67% of late-replicating regions) are characterized as a class of sequences that appear heterogeneous in terms of their decompactization. These fragments are enriched with enhancer sequences and binding sites for insulator proteins. They likely mark the chromatin state that is related to the binding of cis-regulatory proteins. Malachite chromatin fragments (11% of late-replicating regions) appear to function as universal transitional regions between two contrasting chromatin states. Namely, they invariably delimit intercalary heterochromatin regions from the adjacent active chromatin of interbands. Malachite fragments also flank aquamarine fragments embedded in the repressed chromatin of late-replicating regions. Significant enrichment of insulator proteins CP190, SU(HW), and MOD2.2 was observed in malachite chromatin. Neither aquamarine nor malachite chromatin types appear to correlate with the positions of highly conserved non-coding elements (HCNE) that are typically replete in intercalary heterochromatin. Malachite chromatin found on the flanks of intercalary heterochromatin regions tends to replicate earlier than the malachite chromatin embedded in intercalary heterochromatin. In other words, there exists a gradient of replication progressing from the flanks of intercalary heterochromatin regions center-wise. The peculiar organization and features of replication in large late-replicating regions are discussed as possible factors shaping the evolutionary stability of intercalary heterochromatin. PMID:27300486

Integration of heterogeneous molecular networks to unravel gene-regulation in Mycobacterium tuberculosis.

PubMed

van Dam, Jesse C J; Schaap, Peter J; Martins dos Santos, Vitor A P; Suárez-Diez, María

2014-09-26

Different methods have been developed to infer regulatory networks from heterogeneous omics datasets and to construct co-expression networks. Each algorithm produces different networks and efforts have been devoted to automatically integrate them into consensus sets. However each separate set has an intrinsic value that is diluted and partly lost when building a consensus network. Here we present a methodology to generate co-expression networks and, instead of a consensus network, we propose an integration framework where the different networks are kept and analysed with additional tools to efficiently combine the information extracted from each network. We developed a workflow to efficiently analyse information generated by different inference and prediction methods. Our methodology relies on providing the user the means to simultaneously visualise and analyse the coexisting networks generated by different algorithms, heterogeneous datasets, and a suite of analysis tools. As a show case, we have analysed the gene co-expression networks of Mycobacterium tuberculosis generated using over 600 expression experiments. Regarding DNA damage repair, we identified SigC as a key control element, 12 new targets for LexA, an updated LexA binding motif, and a potential mismatch repair system. We expanded the DevR regulon with 27 genes while identifying 9 targets wrongly assigned to this regulon. We discovered 10 new genes linked to zinc uptake and a new regulatory mechanism for ZuR. The use of co-expression networks to perform system level analysis allows the development of custom made methodologies. As show cases we implemented a pipeline to integrate ChIP-seq data and another method to uncover multiple regulatory layers. Our workflow is based on representing the multiple types of information as network representations and presenting these networks in a synchronous framework that allows their simultaneous visualization while keeping specific associations from the different networks. By simultaneously exploring these networks and metadata, we gained insights into regulatory mechanisms in M. tuberculosis that could not be obtained through the separate analysis of each data type.

Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity

PubMed Central

Dalmasso, Giovanni; Marin Zapata, Paula Andrea; Brady, Nathan Ryan; Hamacher-Brady, Anne

2017-01-01

Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological and mobility dynamics are essential for maintaining mitochondrial functional homeostasis, and alterations both impact and reflect cellular stress states. Mitochondrial homeostasis is further dependent on production (biogenesis) and the removal of damaged mitochondria by selective autophagy (mitophagy). While mitochondrial function, dynamics, biogenesis and mitophagy are highly-integrated processes, it is not fully understood how systemic control in the cell is established to maintain homeostasis, or respond to bioenergetic demands. Here we used agent-based modeling (ABM) to integrate molecular and imaging knowledge sets, and simulate population dynamics of mitochondria and their response to environmental energy demand. Using high-dimensional parameter searches we integrated experimentally-measured rates of mitochondrial biogenesis and mitophagy, and using sensitivity analysis we identified parameter influences on population homeostasis. By studying the dynamics of cellular subpopulations with distinct mitochondrial masses, our approach uncovered system properties of mitochondrial populations: (1) mitochondrial fusion and fission activities rapidly establish mitochondrial sub-population homeostasis, and total cellular levels of mitochondria alter fusion and fission activities and subpopulation distributions; (2) restricting the directionality of mitochondrial mobility does not alter morphology subpopulation distributions, but increases network transmission dynamics; and (3) maintaining mitochondrial mass homeostasis and responding to bioenergetic stress requires the integration of mitochondrial dynamics with the cellular bioenergetic state. Finally, (4) our model suggests sources of, and stress conditions amplifying, cell-to-cell variability of mitochondrial morphology and energetic stress states. Overall, our modeling approach integrates biochemical and imaging knowledge, and presents a novel open-modeling approach to investigate how spatial and temporal mitochondrial dynamics contribute to functional homeostasis, and how subcellular organelle heterogeneity contributes to the emergence of cell heterogeneity. PMID:28060865

Covered self-expandable metal stents with an anti-migration system improve patency duration without increased complications compared with uncovered stents for distal biliary obstruction caused by pancreatic carcinoma: a randomized multicenter trial.

PubMed

Kitano, Masayuki; Yamashita, Yukitaka; Tanaka, Kiyohito; Konishi, Hideyuki; Yazumi, Shujiro; Nakai, Yoshitaka; Nishiyama, Osamu; Uehara, Hiroyuki; Mitoro, Akira; Sanuki, Tsuyoshi; Takaoka, Makoto; Koshitani, Tatsuya; Arisaka, Yoshifumi; Shiba, Masatsugu; Hoki, Noriyuki; Sato, Hideki; Sasaki, Yuichi; Sato, Masako; Hasegawa, Kazunori; Kawabata, Hideaki; Okabe, Yoshihiro; Mukai, Hidekazu

2013-11-01

The requirements of biliary stents used in the palliation of malignant biliary obstruction are a long duration of patency and minimal adverse effects. Covered self-expandable metal stents (SEMSs) have been shown to prevent tumor ingrowth, which is the most frequent complication of uncovered SEMSs. However, because they are prone to migration, the superiority of covered SEMS has yet to be convincingly demonstrated. The aim of this study was to evaluate the superiority of covered over uncovered SEMSs in the palliation of distal biliary obstruction due to unresectable pancreatic carcinoma, using both stent types with relatively low axial force and uncovered flared ends to prevent their migration. From April 2009 to December 2010, 120 patients who were admitted to 22 tertiary-care centers because of distal biliary obstruction from unresectable pancreatic carcinomas were enrolled in this prospective randomized multicenter study. Patients were randomly assigned to receive a covered or uncovered SEMS deployed at the site of the biliary stricture during endoscopic retrograde cholangiopancreatography. Stent patency time, patient survival time, patient survival time without stent dysfunction (time to stent dysfunction or patient death), cause of stent dysfunction (ingrowth, overgrowth, migration, or sludge formation), and serious adverse events were compared between covered and uncovered SEMS groups. Patient survival time in the two groups did not significantly differ (median: 285 and 223 days, respectively; P=0.68). Patient survival time without stent dysfunction was significantly longer in the covered than in the uncovered SEMS group (median: 187 vs. 132 days; P=0.043). Stent patency was also significantly longer in the covered than in the uncovered SEMS group (mean±s.d.: 219.3±159.1 vs. 166.9±124.9 days; P=0.047). Reintervention for stent dysfunction was performed in 14 of 60 patients with covered SEMSs (23%) and in 22 of 60 patients with uncovered SEMSs (37%; P=0.08). Stent dysfunction was caused by tumor ingrowth, tumor overgrowth, and sludge formation in 0 (0%), 3 (5%), and 11 (18%) patients in the covered SEMSs group, and in 15 (25%), 2 (3%), and 6 (10%) patients in the uncovered SEMSs group, respectively. Stent migration was not observed in either group. Rates of tumor overgrowth and sludge formation did not significantly differ between the two groups, whereas the rate of tumor ingrowth was significantly lower in the covered than in the uncovered SEMS group (P<0.01). Acute pancreatitis occurred in only one patient in the covered SEMS group. Acute cholecystitis occurred in one patient in the covered SEMS group and in two patients in the uncovered SEMS group. There was no significant difference between the two groups in the incidence of serious adverse events. By preventing tumor ingrowth and migration, covered SEMSs with an anti-migration system had a longer duration of patency than uncovered SEMSs, which recommends their use in the palliative treatment of patients with biliary obstruction due to pancreatic carcinomas.

Familial Brugada syndrome uncovered by hyperkalaemic diabetic ketoacidosis.

PubMed

Postema, Pieter G; Vlaar, Alexander P J; DeVries, J Hans; Tan, Hanno L

2011-10-01

We describe a case of diabetic ketoacidosis with concomitant hyperkalaemia that uncovered a typical Brugada syndrome electrocardiogram (ECG). Further provocation testing in the patient and his son confirmed familial Brugada syndrome. Diabetic ketoacidosis with hyperkalaemia may uncover an inheritable arrhythmia syndrome that may put the patient and his/her next of kin at risk for a sudden death, irrespective of diabetes mellitus.

Can animal habitat use patterns influence their vulnerability to extreme climate events? An estuarine sportfish case study.

PubMed

Boucek, Ross E; Heithaus, Michael R; Santos, Rolando; Stevens, Philip; Rehage, Jennifer S

2017-10-01

Global climate forecasts predict changes in the frequency and intensity of extreme climate events (ECEs). The capacity for specific habitat patches within a landscape to modulate stressors from extreme climate events, and animal distribution throughout habitat matrices during events, could influence the degree of population level effects following the passage of ECEs. Here, we ask (i) does the intensity of stressors of an ECE vary across a landscape? And (ii) Do habitat use patterns of a mobile species influence their vulnerability to ECEs? Specifically, we measured how extreme cold spells might interact with temporal variability in habitat use to affect populations of a tropical, estuarine-dependent large-bodied fish Common Snook, within Everglades National Park estuaries (FL US). We examined temperature variation across the estuary during cold disturbances with different degrees of severity, including an extreme cold spell. Second, we quantified Snook distribution patterns when the passage of ECEs is most likely to occur from 2012 to 2016 using passive acoustic tracking. Our results revealed spatial heterogeneity in the intensity of temperature declines during cold disturbances, with some habitats being consistently 3-5°C colder than others. Surprisingly, Snook distributions during periods of greatest risk to experience an extreme cold event varied among years. During the winters of 2013-2014 and 2014-2015 a greater proportion of Snook occurred in the colder habitats, while the winters of 2012-2013 and 2015-2016 featured more Snook observed in the warmest habitats. This study shows that Snook habitat use patterns could influence vulnerability to extreme cold events, however, whether Snook habitat use increases or decreases their vulnerability to disturbance depends on the year, creating temporally dynamic vulnerability. Faunal global change research should address the spatially explicit nature of extreme climate events and animal habitat use patterns to identify potential mechanisms that may influence population effects following these disturbances. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Unravelling textural heterogeneity in obsidian: Shear-induced outgassing in the Rocche Rosse flow

NASA Astrophysics Data System (ADS)

Shields, J. K.; Mader, H. M.; Caricchi, L.; Tuffen, H.; Mueller, S.; Pistone, M.; Baumgartner, L.

2016-01-01

Obsidian flow emplacement is a complex and understudied aspect of silicic volcanism. Of particular importance is the question of how highly viscous magma can lose sufficient gas in order to erupt effusively as a lava flow. Using an array of methods we study the extreme textural heterogeneity of the Rocche Rosse obsidian flow in Lipari, a 2 km long, 100 m thick, ~ 800 year old lava flow, with respect to outgassing and emplacement mechanisms. 2D and 3D vesicle analyses and density measurements are used to classify the lava into four textural types: 'glassy' obsidian (< 15% vesicles), 'pumiceous' lava (> 40% vesicles), high aspect ratio, 'shear banded' lava (20-40% vesicles) and low aspect ratio, 'frothy' obsidian with 30-60% vesicles. Textural heterogeneity is observed on all scales (m to μm) and occurs as the result of strongly localised strain. Magnetic fabric, described by oblate and prolate susceptibility ellipsoids, records high and variable degrees of shearing throughout the flow. Total water contents are derived using both thermogravimetry and infrared spectroscopy to quantify primary (magmatic) and secondary (meteoric) water. Glass water contents are between 0.08-0.25 wt.%. Water analysis also reveals an increase in water content from glassy obsidian bands towards 'frothy' bands of 0.06-0.08 wt.%, reflecting preferential vesiculation of higher water bands and an extreme sensitivity of obsidian degassing to water content. We present an outgassing model that reconciles textural, volatile and magnetic data to indicate that obsidian is generated from multiple shear-induced outgassing cycles, whereby vesicular magma outgasses and densifies through bubble collapse and fracture healing to form obsidian, which then re-vesiculates to produce 'dry' vesicular magma. Repetition of this cycle throughout magma ascent results in the low water contents of the Rocche Rosse lavas and the final stage in the degassing cycle determines final lava porosity. Heterogeneities in lava rheology (vesicularity, water content, microlite content, viscosity) play a vital role in the structural evolution of an obsidian flow and overprint flow-scale morphology. Post-emplacement hydration also depends heavily on local strain, whereby connectivity of vesicles as a result of shear deformation governs sample rehydration by meteoric water, a process previously correlated to lava vesicularity alone.

Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

PubMed Central

Loos, Ruth J. F.; Kronenberg, Florian; Adamkova, Vera; Anand, Sonia S.; Ardlie, Kristin; Biebermann, Heike; Bjerregaard, Peter; Boeing, Heiner; Bouchard, Claude; Ciullo, Marina; Cooper, Jackie A.; Corella, Dolores; Dina, Christian; Engert, James C.; Fisher, Eva; Francès, Francesc; Froguel, Philippe; Hebebrand, Johannes; Hegele, Robert A.; Hinney, Anke; Hoehe, Margret R.; Hu, Frank B.; Hubacek, Jaroslav A.; Humphries, Steve E.; Hunt, Steven C.; Illig, Thomas; Järvelin, Marjo-Riita; Kaakinen, Marika; Kollerits, Barbara; Krude, Heiko; Kumar, Jitender; Lange, Leslie A.; Langer, Birgit; Li, Shengxu; Luchner, Andreas; Lyon, Helen N.; Meyre, David; Mohlke, Karen L.; Mooser, Vincent; Nebel, Almut; Nguyen, Thuy Trang; Paulweber, Bernhard; Perusse, Louis; Qi, Lu; Rankinen, Tuomo; Rosskopf, Dieter; Schreiber, Stefan; Sengupta, Shantanu; Sorice, Rossella; Suk, Anita; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Völzke, Henry; Vimaleswaran, Karani S.; Wareham, Nicholas J.; Waterworth, Dawn; Yusuf, Salim; Lindgren, Cecilia; McCarthy, Mark I.; Lange, Christoph; Hirschhorn, Joel N.

2009-01-01

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far. PMID:19851442

Uncovering extreme AGN variability in serendipitous X-ray source surveys

NASA Astrophysics Data System (ADS)

Moran, Edward C.; Garcia Soto, Aylin; LaMassa, Stephanie; Urry, Meg

2018-01-01

Constraints on the duty cycle and duration of accretion episodes in active galactic nuclei (AGNs) are vital for establishing how most AGNs are fueled, which is essential for a complete picture of black hole/galaxy co-evolution. Perhaps the best handle we have on these activity parameters is provided by AGNs that have displayed dramatic changes in their bolometric luminosities and, in some cases, spectroscopic classifications. Given that X-ray emission is directly linked to black-hole accretion, X-ray surveys should provide a straightforward means of identifying AGNs that have undergone dramatic changes in their accretion states. However, it appears that such events are very rare, so wide-area surveys separated in time by many years are needed to maximize discovery rates. We have cross-correlated the Einstein IPC Two-Sigma Catalog with the ROSAT All-Sky Survey Faint Source Catalog to identify a sample of soft X-ray sources that varied by factors ranging from 7 to more than 100 over a ten year timescale. When possible, we have constructed long-term X-ray light curves for the sources by combining the Einstein and RASS fluxes with those obtained from serendipitous pointed observations by ROSAT, Chandra,XMM, and Swift. Optical follow-up observations indicate that many of the extremely variable sources in our sample are indeed radio-quiet AGNs. Interestingly, the majority of objects that dimmed between ~1980 and ~1990 are still (or are again) broad-line AGNs rather than“changing-look” candidates that have more subtle AGN signatures in their spectra — despite the fact that none of the sources examined thus far has returned to its highest observed luminosity. Future X-ray observations will provide the opportunity to characterize the X-ray behavior of these anonymous, extreme AGNs over a four decade span.

New insights in the bacterial spore resistance to extreme terrestrial and extraterrestrial factors

NASA Astrophysics Data System (ADS)

Moeller, Ralf; Horneck, Gerda; Reitz, Guenther

Based on their unique resistance to various space parameters, Bacillus endospores are one of the model systems used for astrobiological studies. The extremely high resistance of bacterial endospores to environmental stress factors has intrigued researchers since long time and many characteristic spore features, especially those involved in the protection of spore DNA, have already been uncovered. The disclosure of the complete genomic sequence of Bacillus subtilis 168, one of the often used astrobiological model system, and the rapid development of tran-scriptional microarray techniques have opened new opportunities of gaining further insights in the enigma of spore resistance. Spores of B. subtilis were exposed to various extreme ter-restrial and extraterrestrial stressors to reach a better understanding of the DNA protection and repair strategies, which them to cope with the induced DNA damage. Following physical stress factors of environmental importance -either on Earth or in space -were selected for this thesis: (i) mono-and polychromatic UV radiation, (ii) ionizing radiation, (iii) exposure to ultrahigh vacuum; and (iv) high shock pressures simulating meteorite impacts. To reach a most comprehensive understanding of spore resistance to those harsh terrestrial or simulated extraterrestrial conditions, a standardized experimental protocol of the preparation and ana-lyzing methods was established including the determination of the following spore responses: (i) survival, (ii) induced mutations, (iii) DNA damage, (iv) role of different repair pathways by use of a set of repair deficient mutants, and (v) transcriptional responses during spore germi-nation by use of genome-wide transcriptome analyses and confirmation by RT-PCR. From this comprehensive set of data on spore resistance to a variety of environmental stress parameters a model of a "built-in" transcriptional program of bacterial spores in response to DNA damaging treatments to ensure DNA restoration during germination has been developed.

A Coupled Approach with Stochastic Rainfall-Runoff Simulation and Hydraulic Modeling for Extreme Flood Estimation on Large Watersheds

NASA Astrophysics Data System (ADS)

Paquet, E.

2015-12-01

The SCHADEX method aims at estimating the distribution of peak and daily discharges up to extreme quantiles. It couples a precipitation probabilistic model based on weather patterns, with a stochastic rainfall-runoff simulation process using a conceptual lumped model. It allows exploring an exhaustive set of hydrological conditions and watershed responses to intense rainfall events. Since 2006, it has been widely applied in France to about one hundred watersheds for dam spillway design, and also aboard (Norway, Canada and central Europe among others). However, its application to large watersheds (above 10 000 km²) faces some significant issues: spatial heterogeneity of rainfall and hydrological processes and flood peak damping due to hydraulic effects (flood plains, natural or man-made embankment) being the more important. This led to the development of an extreme flood simulation framework for large and heterogeneous watersheds, based on the SCHADEX method. Its main features are: Division of the large (or main) watershed into several smaller sub-watersheds, where the spatial homogeneity of the hydro-meteorological processes can reasonably be assumed, and where the hydraulic effects can be neglected. Identification of pilot watersheds where discharge data are available, thus where rainfall-runoff models can be calibrated. They will be parameters donors to non-gauged watersheds. Spatially coherent stochastic simulations for all the sub-watersheds at the daily time step. Identification of a selection of simulated events for a given return period (according to the distribution of runoff volumes at the scale of the main watershed). Generation of the complete hourly hydrographs at each of the sub-watersheds outlets. Routing to the main outlet with hydraulic 1D or 2D models. The presentation will be illustrated with the case-study of the Isère watershed (9981 km), a French snow-driven watershed. The main novelties of this method will be underlined, as well as its perspectives and future improvements.

Rank score and permutation testing alternatives for regression quantile estimates

USGS Publications Warehouse

Cade, B.S.; Richards, J.D.; Mielke, P.W.

2006-01-01

Performance of quantile rank score tests used for hypothesis testing and constructing confidence intervals for linear quantile regression estimates (0 ≤ τ ≤ 1) were evaluated by simulation for models with p = 2 and 6 predictors, moderate collinearity among predictors, homogeneous and hetero-geneous errors, small to moderate samples (n = 20–300), and central to upper quantiles (0.50–0.99). Test statistics evaluated were the conventional quantile rank score T statistic distributed as χ2 random variable with q degrees of freedom (where q parameters are constrained by H 0:) and an F statistic with its sampling distribution approximated by permutation. The permutation F-test maintained better Type I errors than the T-test for homogeneous error models with smaller n and more extreme quantiles τ. An F distributional approximation of the F statistic provided some improvements in Type I errors over the T-test for models with > 2 parameters, smaller n, and more extreme quantiles but not as much improvement as the permutation approximation. Both rank score tests required weighting to maintain correct Type I errors when heterogeneity under the alternative model increased to 5 standard deviations across the domain of X. A double permutation procedure was developed to provide valid Type I errors for the permutation F-test when null models were forced through the origin. Power was similar for conditions where both T- and F-tests maintained correct Type I errors but the F-test provided some power at smaller n and extreme quantiles when the T-test had no power because of excessively conservative Type I errors. When the double permutation scheme was required for the permutation F-test to maintain valid Type I errors, power was less than for the T-test with decreasing sample size and increasing quantiles. Confidence intervals on parameters and tolerance intervals for future predictions were constructed based on test inversion for an example application relating trout densities to stream channel width:depth.

Comparison of outcomes among secondary covered metallic, uncovered metallic, and plastic biliary stents in treating occluded primary metallic stents in malignant distal biliary obstruction.

PubMed

Cho, Jae Hee; Jeon, Tae Joo; Park, Jeong Youp; Kim, Hee Man; Kim, Yoon Jae; Park, Seung Woo; Chung, Jae Bock; Song, Si Young; Bang, Seungmin

2011-02-01

The self-expandable metallic stent (SEMS) has been widely used for unresectable malignant biliary obstruction but eventually becomes occluded by tumor ingrowth/overgrowth and sludge. Therefore, we aimed to determine the therapeutic effectiveness of secondary stents and to find differences according to various combinations of the first and second stents for the management of occluded SEMSs in patients with malignant distal biliary obstruction. Between 1999 and November 2008, 77 patients with malignant biliary obstruction underwent secondary biliary stent placement as "stent-in-stent" at three university hospitals in Korea (40 covered, 26 uncovered, and 11 plastic stents). The membrane of the covered SEMS was regarded as the barrier against tumor ingrowth. We categorized the patients into three groups based on whether the covered SEMS was either the first or the second stent: membrane-SEMS (18 covered-covered; 9 covered-uncovered; 22 uncovered-covered SEMS), bare-SEMS (17 uncovered-uncovered SEMS), and plastic stent (3 covered-plastic; 8 uncovered-plastic). The median patency of second stents was 138, 109, and 88 days (covered, uncovered, and plastic stents). The second covered SEMSs had a significantly longer patency than plastic stents (p=0.047). In a multivariate analysis including membrane-SEMS, bare-SEMS, and plastic stent groups, the bare-SEMS had a worse cumulative stent patency (HR=2.04, CI=1.08-3.86) and survival time (HR=2.37, CI=1.25-4.49) than the membrane-SEMS. Patients with ampulla of Vater cancer had better stent patency (HR=0.27, CI=0.08-0.98) and survival (HR=0.17, CI=0.04-0.77) than those with other pancreatobiliary malignancies. In addition, antitumor treatment prolonged survival time (HR=0.50, CI=0.26-0.99). The placement of additional biliary stents using the "stent-in-stent" method is an effective treatment for an occluded metallic primary stent. In addition, double biliary SEMS placement using at least one covered SEMS (in the primary and/or secondary procedure) might provide longer cumulative stent patency and survival than using uncovered SEMSs in both procedures.

Concurrent Increases and Decreases in Local Stability and Conformational Heterogeneity in Cu, Zn Superoxide Dismutase Variants Revealed by Temperature-Dependence of Amide Chemical Shifts.

PubMed

Doyle, Colleen M; Rumfeldt, Jessica A; Broom, Helen R; Sekhar, Ashok; Kay, Lewis E; Meiering, Elizabeth M

2016-03-08

The chemical shifts of backbone amide protons in proteins are sensitive reporters of local structural stability and conformational heterogeneity, which can be determined from their readily measured linear and nonlinear temperature-dependences, respectively. Here we report analyses of amide proton temperature-dependences for native dimeric Cu, Zn superoxide dismutase (holo pWT SOD1) and structurally diverse mutant SOD1s associated with amyotrophic lateral sclerosis (ALS). Holo pWT SOD1 loses structure with temperature first at its periphery and, while having extremely high global stability, nevertheless exhibits extensive conformational heterogeneity, with ∼1 in 5 residues showing evidence for population of low energy alternative states. The holo G93A and E100G ALS mutants have moderately decreased global stability, whereas V148I is slightly stabilized. Comparison of the holo mutants as well as the marginally stable immature monomeric unmetalated and disulfide-reduced (apo(2SH)) pWT with holo pWT shows that changes in the local structural stability of individual amides vary greatly, with average changes corresponding to differences in global protein stability measured by differential scanning calorimetry. Mutants also exhibit altered conformational heterogeneity compared to pWT. Strikingly, substantial increases as well as decreases in local stability and conformational heterogeneity occur, in particular upon maturation and for G93A. Thus, the temperature-dependence of amide shifts for SOD1 variants is a rich source of information on the location and extent of perturbation of structure upon covalent changes and ligand binding. The implications for potential mechanisms of toxic misfolding of SOD1 in disease and for general aspects of protein energetics, including entropy-enthalpy compensation, are discussed.

Nucleation and dynamic rupture on weakly stressed faults sustained by thermal pressurization

NASA Astrophysics Data System (ADS)

Schmitt, Stuart V.; Segall, Paul; Dunham, Eric M.

2015-11-01

Earthquake nucleation requires that the shear stress τ locally reaches a fault's static strength, fσeff, the product of the friction coefficient and effective normal stress. Once rupture initiates, shear heating-induced thermal pressurization can sustain rupture at much lower τ/σeff ratios, a stress condition believed to be the case during most earthquakes. This requires that earthquakes nucleate at heterogeneities. We model nucleation and dynamic rupture on faults in a 2-D elastic medium with rate/state friction and thermal pressurization, subjected to globally low τ but with local stress heterogeneities that permit nucleation. We examine end-member cases of either high-τ or low-σeff heterogeneities. We find that thermal pressurization can sustain slip at τ/σeff values as low as 0.13, compared to static friction of ˜0.7. Background τ (and, to lesser extent, heterogeneity width) controls whether ruptures arrest or are sustained, with extremely low values resulting in arrest. For a small range of background τ, sustained slip is pulse-like. Cessation of slip in a pulse tail can result from either diffusive restrengthening of σeff or a wave-mediated stopping phase that follows the rupture tip. Slightly larger background τ leads to sustained crack-like rupture. Thermal pressurization is stronger at high-τ heterogeneities, resulting in a lower background τ threshold for sustained rupture and potentially larger arresting ruptures. High-stress events also initiate with higher moment rate, although this may be difficult to observe in nature. For arresting ruptures, stress drops and the dependence of fracture energy on mean slip are both consistent with values inferred for small earthquakes.

Flow cytometry and cell sorting of heterogeneous microbial populations: the importance of single-cell analyses.

PubMed Central

Davey, H M; Kell, D B

1996-01-01

The most fundamental questions such as whether a cell is alive, in the sense of being able to divide or to form a colony, may sometimes be very hard to answer, since even axenic microbial cultures are extremely heterogeneous. Analyses that seek to correlate such things as viability, which is a property of an individual cell, with macroscopic measurements of culture variables such as ATP content, respiratory activity, and so on, must inevitably fail. It is therefore necessary to make physiological measurements on individual cells. Flow cytometry is such a technique, which allows one to analyze cells rapidly and individually and permits the quantitative analysis of microbial heterogeneity. It therefore offers many advantages over conventional measurements for both routine and more exploratory analyses of microbial properties. While the technique has been widely applied to the study of mammalian cells, is use in microbiology has until recently been much more limited, largely because of the smaller size of microbes and the consequently smaller optical signals obtainable from them. Since these technical barriers no longer hold, flow cytometry with appropriate stains has been used for the rapid discrimination and identification of microbial cells, for the rapid assessment of viability and of the heterogeneous distributions of a wealth of other more detailed physiological properties, for the analysis of antimicrobial drug-cell interactions, and for the isolation of high-yielding strains of biotechnological interest. Flow cytometric analyses provide an abundance of multivariate data, and special methods have been devised to exploit these. Ongoing advances mean that modern flow cytometers may now be used by nonspecialists to effect a renaissance in our understanding of microbial heterogeneity. PMID:8987359

Mesoarchean melting and Neoarchean to Paleoproterozoic metasomatism during the formation of the cratonic mantle keel beneath West Greenland

NASA Astrophysics Data System (ADS)

van Acken, D.; Luguet, A.; Pearson, D. G.; Nowell, G. M.; Fonseca, R. O. C.; Nagel, T. J.; Schulz, T.

2017-04-01

Highly siderophile element (HSE) concentration and 187Os/188Os isotopic heterogeneity has been observed on various scales in the Earth's mantle. Interaction of residual mantle peridotite with infiltrating melts has been suggested to overprint primary bulk rock HSE signatures originating from partial melting, contributing to the heterogeneity seen in the global peridotite database. Here we present a detailed study of harzburgitic xenolith 474527 from the Kangerlussuaq suite, West Greenland, coupling the Re-Os isotope geochemistry with petrography of both base metal sulfides (BMS) and silicates to assess the impact of overprint induced by melt-rock reaction on the Re-Os isotope system. Garnet harzburgite sample 474527 shows considerable heterogeneity in the composition of its major phases, most notably olivine and Cr-rich garnet, suggesting formation through multiple stages of partial melting and subsequent metasomatic events. The major BMS phases show a fairly homogeneous pentlandite-rich composition typical for BMS formed via metasomatic reaction, whereas the 187Os/188Os compositions determined for 17 of these BMS are extremely heterogeneous ranging between 0.1037 and 0.1981. Analyses by LA-ICP-MS reveal at least two populations of BMS grains characterized by contrasting HSE patterns. One type of pattern is strongly enriched in the more compatible HSE Os, Ir, and Ru over the typically incompatible Pt, Pd, and Re, while the other type shows moderate enrichment of the more incompatible HSE and has overall lower compatible HSE/incompatible HSE composition. The small-scale heterogeneity observed in these BMS highlights the need for caution when utilizing the Re-Os system to date mantle events, as even depleted harzburgite samples such as 474527 are likely to have experienced a complex history of metasomatic overprinting, with uncertain effects on the HSE.

State-of-the-art Nanofabrication in Catalysis.

PubMed

Karim, Waiz; Tschupp, Simon A; Herranz, Juan; Schmidt, Thomas J; Ekinci, Yasin; van Bokhovenac, Jeroen A

2017-04-26

We present recent developments in top-down nanofabrication that have found application in catalysis research. To unravel the complexity of catalytic systems, the design and use of models with control of size, morphology, shape and inter-particle distances is a necessity. The study of well-defined and ordered nanoparticles on a support contributes to the understanding of complex phenomena that govern reactions in heterogeneous and electro-catalysis. We review the strengths and limitations of different nanolithography methods such as electron beam lithography (EBL), photolithography, extreme ultraviolet (EUV) lithography and colloidal lithography for the creation of such highly tunable catalytic model systems and their applications in catalysis. Innovative strategies have enabled particle sizes reaching dimensions below 10 nm. It is now possible to create pairs of particles with distance controlled with an extremely high precision in the order of one nanometer. We discuss our approach to study these model systems at the single-particle level using X-ray absorption spectroscopy and show new ways to fabricate arrays of single nanoparticles or nanoparticles in pairs over a large area using EBL and EUV-achromatic Talbot lithography. These advancements have provided new insights into the active sites in metal catalysts and enhanced the understanding of the role of inter-particle interactions and catalyst supports, such as in the phenomenon of hydrogen spillover. We present a perspective on future directions for employing top-down nanofabrication in heterogeneous and electrocatalysis. The rapid development in nanofabrication and characterization methods will continue to have an impact on understanding of complex catalytic processes.

Earth Science Data Analytics: Preparing for Extracting Knowledge from Information

NASA Technical Reports Server (NTRS)

Kempler, Steven; Barbieri, Lindsay

2016-01-01

Data analytics is the process of examining large amounts of data of a variety of types to uncover hidden patterns, unknown correlations and other useful information. Data analytics is a broad term that includes data analysis, as well as an understanding of the cognitive processes an analyst uses to understand problems and explore data in meaningful ways. Analytics also include data extraction, transformation, and reduction, utilizing specific tools, techniques, and methods. Turning to data science, definitions of data science sound very similar to those of data analytics (which leads to a lot of the confusion between the two). But the skills needed for both, co-analyzing large amounts of heterogeneous data, understanding and utilizing relevant tools and techniques, and subject matter expertise, although similar, serve different purposes. Data Analytics takes on a practitioners approach to applying expertise and skills to solve issues and gain subject knowledge. Data Science, is more theoretical (research in itself) in nature, providing strategic actionable insights and new innovative methodologies. Earth Science Data Analytics (ESDA) is the process of examining, preparing, reducing, and analyzing large amounts of spatial (multi-dimensional), temporal, or spectral data using a variety of data types to uncover patterns, correlations and other information, to better understand our Earth. The large variety of datasets (temporal spatial differences, data types, formats, etc.) invite the need for data analytics skills that understand the science domain, and data preparation, reduction, and analysis techniques, from a practitioners point of view. The application of these skills to ESDA is the focus of this presentation. The Earth Science Information Partners (ESIP) Federation Earth Science Data Analytics (ESDA) Cluster was created in recognition of the practical need to facilitate the co-analysis of large amounts of data and information for Earth science. Thus, from a to advance science point of view: On the continuum of ever evolving data management systems, we need to understand and develop ways that allow for the variety of data relationships to be examined, and information to be manipulated, such that knowledge can be enhanced, to facilitate science. Recognizing the importance and potential impacts of the unlimited ways to co-analyze heterogeneous datasets, now and especially in the future, one of the objectives of the ESDA cluster is to facilitate the preparation of individuals to understand and apply needed skills to Earth science data analytics. Pinpointing and communicating the needed skills and expertise is new, and not easy. Information technology is just beginning to provide the tools for advancing the analysis of heterogeneous datasets in a big way, thus, providing opportunity to discover unobvious scientific relationships, previously invisible to the science eye. And it is not easy It takes individuals, or teams of individuals, with just the right combination of skills to understand the data and develop the methods to glean knowledge out of data and information. In addition, whereas definitions of data science and big data are (more or less) available (summarized in Reference 5), Earth science data analytics is virtually ignored in the literature, (barring a few excellent sources).

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

PubMed Central

Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M.; van Meurs, Joyce B.J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M.; Kiemeney, Lambertus A.; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F.; Martin, Nicholas G.; Metspalu, Andres; Morris, Andrew D.; Nieminen, Markku S.; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Ouwehand, Willem H.; Palmer, Lyle J.; Penninx, Brenda; Power, Chris; Province, Michael A.; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M.; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J.; Snieder, Harold; Sørensen, Thorkild I.A.; Spector, Timothy D.; Stefansson, Kari; Tönjes, Anke; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; van der Harst, Pim; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Wichmann, H.-Erich; Wilson, James F.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunian, Talin; Heid, Iris M.; Hunter, David; Kaplan, Robert C.; Karpe, Fredrik; Moffatt, Miriam; Mohlke, Karen L.; O’Connell, Jeffrey R.; Pawitan, Yudi; Schadt, Eric E.; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P.; Thorsteinsdottir, Unnur; van Duijn, Cornelia M.; Visscher, Peter M.; Di Blasio, Anna Maria; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Morris, Andrew P.; Meyre, David; Scherag, André; McCarthy, Mark I.; Speliotes, Elizabeth K.; North, Kari E.; Loos, Ruth J.F.; Ingelsson, Erik

2014-01-01

Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups. PMID:23563607

Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

PubMed

von Mehren, Margaret; Randall, R Lor; Benjamin, Robert S; Boles, Sarah; Bui, Marilyn M; Ganjoo, Kristen N; George, Suzanne; Gonzalez, Ricardo J; Heslin, Martin J; Kane, John M; Keedy, Vicki; Kim, Edward; Koon, Henry; Mayerson, Joel; McCarter, Martin; McGarry, Sean V; Meyer, Christian; Morris, Zachary S; O'Donnell, Richard J; Pappo, Alberto S; Paz, I Benjamin; Petersen, Ivy A; Pfeifer, John D; Riedel, Richard F; Ruo, Bernice; Schuetze, Scott; Tap, William D; Wayne, Jeffrey D; Bergman, Mary Anne; Scavone, Jillian L

2018-05-01

Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for STS provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumors, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis, staging, and treatment of STS of the extremities, superficial trunk, or head and neck; outlines treatment recommendations by disease stage; and reviews the evidence to support the guidelines recommendations. Copyright © 2018 by the National Comprehensive Cancer Network.

Environmental heterogeneity and biotic interactions mediate climate impacts on tropical forest regeneration.

PubMed

Uriarte, María; Muscarella, Robert; Zimmerman, Jess K

2018-02-01

Predicting the fate of tropical forests under a changing climate requires understanding species responses to climatic variability and extremes. Seedlings may be particularly vulnerable to climatic stress given low stored resources and undeveloped roots; they also portend the potential effects of climate change on future forest composition. Here we use data for ca. 50,000 tropical seedlings representing 25 woody species to assess (i) the effects of interannual variation in rainfall and solar radiation between 2007 and 2016 on seedling survival over 9 years in a subtropical forest; and (ii) how spatial heterogeneity in three environmental factors-soil moisture, understory light, and conspecific neighborhood density-modulate these responses. Community-wide seedling survival was not sensitive to interannual rainfall variability but interspecific variation in these responses was large, overwhelming the average community response. In contrast, community-wide responses to solar radiation were predominantly positive. Spatial heterogeneity in soil moisture and conspecific density were the predominant and most consistent drivers of seedling survival, with the majority of species exhibiting greater survival at low conspecific densities and positive or nonlinear responses to soil moisture. This environmental heterogeneity modulated impacts of rainfall and solar radiation. Negative conspecific effects were amplified during rainy years and at dry sites, whereas the positive effects of radiation on survival were more pronounced for seedlings existing at high understory light levels. These results demonstrate that environmental heterogeneity is not only the main driver of seedling survival in this forest but also plays a central role in buffering or exacerbating impacts of climate fluctuations on forest regeneration. Since seedlings represent a key bottleneck in the demographic cycle of trees, efforts to predict the long-term effects of a changing climate on tropical forests must take into account this environmental heterogeneity and how its effects on regeneration dynamics play out in long-term stand dynamics. © 2017 John Wiley & Sons Ltd.

Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior

PubMed Central

Tomiyasu, Hirotaka; Garbe, John R.; Cornax, Ingrid; Amaya, Clarissa; O'Sullivan, M. Gerard; Subramanian, Subbaya

2016-01-01

ABSTRACT Osteosarcoma (OS) is a heterogeneous and rare disease with a disproportionate impact because it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed. For this study, we used cell lines derived from two spontaneous canine OS tumors with distinctly different biological behavior (OS-1 and OS-2) for heterotypic in vivo modeling that recapitulates the heterogeneous biology and behavior of this disease. Both cell lines demonstrated stability of the transcriptome when grown as orthotopic xenografts in athymic nude mice. Consistent with the behavior of the original tumors, OS-2 xenografts grew more rapidly at the primary site and had greater propensity to disseminate to lung and establish microscopic metastasis. Moreover, OS-2 promoted formation of a different tumor-associated stromal environment than OS-1 xenografts. OS-2-derived tumors comprised a larger percentage of the xenograft tumors than OS-1-derived tumors. In addition, a robust pro-inflammatory population dominated the stromal cell infiltrates in OS-2 xenografts, whereas a mesenchymal population with a gene signature reflecting myogenic signaling dominated those in the OS-1 xenografts. Our studies show that canine OS cell lines maintain intrinsic features of the tumors from which they were derived and recapitulate the heterogeneous biology and behavior of bone cancer in mouse models. This system provides a resource to understand essential interactions between tumor cells and the stromal environment that drive the progression and metastatic propensity of OS. PMID:27874835

Large-scale compositional heterogeneity in the Earth's mantle

NASA Astrophysics Data System (ADS)

Ballmer, M.

2017-12-01

Seismic imaging of subducted Farallon and Tethys lithosphere in the lower mantle has been taken as evidence for whole-mantle convection, and efficient mantle mixing. However, cosmochemical constraints point to a lower-mantle composition that has a lower Mg/Si compared to upper-mantle pyrolite. Moreover, geochemical signatures of magmatic rocks indicate the long-term persistence of primordial reservoirs somewhere in the mantle. In this presentation, I establish geodynamic mechanisms for sustaining large-scale (primordial) heterogeneity in the Earth's mantle using numerical models. Mantle flow is controlled by rock density and viscosity. Variations in intrinsic rock density, such as due to heterogeneity in basalt or iron content, can induce layering or partial layering in the mantle. Layering can be sustained in the presence of persistent whole mantle convection due to active "unmixing" of heterogeneity in low-viscosity domains, e.g. in the transition zone or near the core-mantle boundary [1]. On the other hand, lateral variations in intrinsic rock viscosity, such as due to heterogeneity in Mg/Si, can strongly affect the mixing timescales of the mantle. In the extreme case, intrinsically strong rocks may remain unmixed through the age of the Earth, and persist as large-scale domains in the mid-mantle due to focusing of deformation along weak conveyor belts [2]. That large-scale lateral heterogeneity and/or layering can persist in the presence of whole-mantle convection can explain the stagnation of some slabs, as well as the deflection of some plumes, in the mid-mantle. These findings indeed motivate new seismic studies for rigorous testing of model predictions. [1] Ballmer, M. D., N. C. Schmerr, T. Nakagawa, and J. Ritsema (2015), Science Advances, doi:10.1126/sciadv.1500815. [2] Ballmer, M. D., C. Houser, J. W. Hernlund, R. Wentzcovitch, and K. Hirose (2017), Nature Geoscience, doi:10.1038/ngeo2898.

Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior.

PubMed

Scott, Milcah C; Tomiyasu, Hirotaka; Garbe, John R; Cornax, Ingrid; Amaya, Clarissa; O'Sullivan, M Gerard; Subramanian, Subbaya; Bryan, Brad A; Modiano, Jaime F

2016-12-01

Osteosarcoma (OS) is a heterogeneous and rare disease with a disproportionate impact because it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed. For this study, we used cell lines derived from two spontaneous canine OS tumors with distinctly different biological behavior (OS-1 and OS-2) for heterotypic in vivo modeling that recapitulates the heterogeneous biology and behavior of this disease. Both cell lines demonstrated stability of the transcriptome when grown as orthotopic xenografts in athymic nude mice. Consistent with the behavior of the original tumors, OS-2 xenografts grew more rapidly at the primary site and had greater propensity to disseminate to lung and establish microscopic metastasis. Moreover, OS-2 promoted formation of a different tumor-associated stromal environment than OS-1 xenografts. OS-2-derived tumors comprised a larger percentage of the xenograft tumors than OS-1-derived tumors. In addition, a robust pro-inflammatory population dominated the stromal cell infiltrates in OS-2 xenografts, whereas a mesenchymal population with a gene signature reflecting myogenic signaling dominated those in the OS-1 xenografts. Our studies show that canine OS cell lines maintain intrinsic features of the tumors from which they were derived and recapitulate the heterogeneous biology and behavior of bone cancer in mouse models. This system provides a resource to understand essential interactions between tumor cells and the stromal environment that drive the progression and metastatic propensity of OS. © 2016. Published by The Company of Biologists Ltd.

Comparison of statistical tests for association between rare variants and binary traits.

PubMed

Bacanu, Silviu-Alin; Nelson, Matthew R; Whittaker, John C

2012-01-01

Genome-wide association studies have found thousands of common genetic variants associated with a wide variety of diseases and other complex traits. However, a large portion of the predicted genetic contribution to many traits remains unknown. One plausible explanation is that some of the missing variation is due to the effects of rare variants. Nonetheless, the statistical analysis of rare variants is challenging. A commonly used method is to contrast, within the same region (gene), the frequency of minor alleles at rare variants between cases and controls. However, this strategy is most useful under the assumption that the tested variants have similar effects. We previously proposed a method that can accommodate heterogeneous effects in the analysis of quantitative traits. Here we extend this method to include binary traits that can accommodate covariates. We use simulations for a variety of causal and covariate impact scenarios to compare the performance of the proposed method to standard logistic regression, C-alpha, SKAT, and EREC. We found that i) logistic regression methods perform well when the heterogeneity of the effects is not extreme and ii) SKAT and EREC have good performance under all tested scenarios but they can be computationally intensive. Consequently, it would be more computationally desirable to use a two-step strategy by (i) selecting promising genes by faster methods and ii) analyzing selected genes using SKAT/EREC. To select promising genes one can use (1) regression methods when effect heterogeneity is assumed to be low and the covariates explain a non-negligible part of trait variability, (2) C-alpha when heterogeneity is assumed to be large and covariates explain a small fraction of trait's variability and (3) the proposed trend and heterogeneity test when the heterogeneity is assumed to be non-trivial and the covariates explain a large fraction of trait variability.

Strategies Influencing Spatial Heterogeneity of Microbial Life in a Soil Lysimeter

NASA Astrophysics Data System (ADS)

Sengupta, A.; Neilson, J. W.; Meira, A.; Wang, Y.; Meza, M.; Chorover, J.; Maier, R. M.; Troch, P. A. A.

2016-12-01

Soil microorganisms are critical drivers of biogeochemical processes. These microbes, in conjunction with their physical and chemical environment, contribute to ecosystem functioning and services of the landscape, have a profound impact on soil formation, and are of particular importance in oligotrophic environments; ecosystems that are characterized by low biotic diversity due to extremely low nutrient levels. Here, we present a study of microbial heterogeneity in a soil lysimeter under incipient conditions. The key questions asked were: 1) what is the spatial heterogeneity of microbes over a new and evolving landscape with inherent oligotrophic conditions, and 2) can patterns in diversity translate to patterns in microbe-mediated weathering processes and soil formation? We hypothesized that stratification of environmental conditions, brought about by varying water potential, flow paths, and redox conditions, will drive the heterogeneity of microbial life in a sub-meter scale. A suite of traditional and current microbiological tools were employed to study community characteristics. These included isolation on R2A media, quantitative polymerase chain reactions targeted at 16S rRNA bacterial and archaeal genes, and 18S fungal genes, and iTAG phylogenetic gene amplification. Illumina Mi-Seq platform generated sequences were analyzed using various bioinformatics pipelines to identify community patterns, classify microbial metabolic functions, and identify variables affecting the community dynamics. Numerous phyla (Verrucomicrobia, Actinobacteria, Planctomycetes, Proteobacteria, and Euryarchaeota) were identified. The surface layer had distinctly different distribution of communities compared to the other layers. Metabolically heterogeneous groups were found with respect to depth, with metabolic functions further confirmed by predictive functional profiling of the microbial communities. Therefore, despite being highly oligotrophic, the system was rich in species and functional diversity. Alongside physical and chemical data, the patterns observed in spatial and functional heterogeneity of microbes under incipient conditions is unique, and allows us to predict strategies undertaken by these microbes to survive in, and influence their oligotrophic environments.

Heterogeneous Sensitivity of Tropical Precipitation Extremes during Growth and Mature Phases of Atmospheric Warming

NASA Astrophysics Data System (ADS)

Parhi, P.; Giannini, A.; Lall, U.; Gentine, P.

2016-12-01

Assessing and managing risks posed by climate variability and change is challenging in the tropics, from both a socio-economic and a scientific perspective. Most of the vulnerable countries with a limited climate adaptation capability are in the tropics. However, climate projections, particularly of extreme precipitation, are highly uncertain there. The CMIP5 (Coupled Model Inter- comparison Project - Phase 5) inter-model range of extreme precipitation sensitivity to the global temperature under climate change is much larger in the tropics as compared to the extra-tropics. It ranges from nearly 0% to greater than 30% across models (O'Gorman 2012). The uncertainty is also large in historical gauge or satellite based observational records. These large uncertainties in the sensitivity of tropical precipitation extremes highlight the need to better understand how tropical precipitation extremes respond to warming. We hypothesize that one of the factors explaining the large uncertainty is due to differing sensitivities during different phases of warming. We consider the `growth' and `mature' phases of warming under climate variability case- typically associated with an El Niño event. In the remote tropics (away from tropical Pacific Ocean), the response of the precipitation extremes during the two phases can be through different pathways: i) a direct and fast changing radiative forcing in an atmospheric column, acting top-down due to the tropospheric warming, and/or ii) an indirect effect via changes in surface temperatures, acting bottom-up through surface water and energy fluxes. We also speculate that the insights gained here might be useful in interpreting the large sensitivity under climate change scenarios, since the physical mechanisms during the two warming phases under climate variability case, have some correspondence with an increasing and stabilized green house gas emission scenarios.

The Gas in Virgo’s “Red and Dead” Dwarf Elliptical Galaxies

NASA Astrophysics Data System (ADS)

Hallenbeck, Gregory L.; Koopmann, Rebecca A.

2017-01-01

As star-forming dwarf irregulars and faint spirals fall onto a cluster, their gas content is easily and quickly removed by ram-pressure stripping or other cluster forces. Residual signs of star formation cease within 100 Myr, and only after approximately 1 Gyr do their optical features transition to elliptical.Despite this, ALFALFA has uncovered a population of three “red and dead” dwarf ellipticals in the Virgo Cluster which still have detectable reservoirs of HI. These dwarf ellipticals are extremely gas-rich—as gas-rich as the cluster’s star-forming dwarf irregulars (Hallenbeck et al. 2012). Where does this gas come from? We consider two possibilities. First, that the gas is recently acquired, and has not yet had time to form stars. Second, that the gas is primordial, and has been disrupted from being able to form stars during the current epoch.We present deep optical (using CFHT and KPNO) and HI (Arecibo and VLA) observations of this sample to demonstrate that this gas is primordial. These observations show that all three galaxies have exponentially decreasing profiles characteristic of dwarf ellipticals and that their rotation velocities are extremely low. However, like more massive elliptical galaxies with HI, these dwarf galaxies show irregular optical morphology. For one target, VCC 190, we additionally observe an HI tail consistent with a recent interaction with the massive spiral galaxy NGC 4224.

Unveiling the extreme nature of the hyper faint galaxy Virgo I

NASA Astrophysics Data System (ADS)

Crnojevic, Denija

2017-08-01

We request HST/ACS imaging to obtain a deep color-magnitude diagram of the newly discovered candidate Milky Way satellite Virgo I. With an estimated absolute magnitude of only M_V -0.8 and a Galactocentric radius of 90 kpc, Virgo I is one of the faintest and most distant dwarfs ever observed, and could be identified as a prototype ''hyper'' faint galaxy. The detailed characterization of the smallest inhabited dark matter subhalos is crucial to guide hierarchical galaxy formation models, and in particular to constrain reionization, the nature of the dark matter particle, etc. With the advent of deep wide-field, ground-based surveys, the potential of uncovering these lowest-mass galaxies is quickly turning into reality, as demonstrated by the discovery in the past two years of tens of new Local Group members in the ultra-faint regime (M_V>-8). Virgo I represents a new record in galaxy physical properties, and urges us to be prepared for the likely emergence of an entirely new class of such objects in the era of future wide-field surveys (e.g., LSST). Only high resolution HST observations can enable us to confirm the nature of Virgo I, providing significantly more accurate estimates for its distance and structural properties, when compared to the discovery Subaru/HyperSuprimeCam imaging. Our proposed dataset will constitute a fundamental step in the upcoming hunt for galaxies with similarly extreme properties.

Hubble Observes One-of-a-Kind Star Nicknamed ‘Nasty’

NASA Image and Video Library

2015-03-21

Astronomers using NASA’s Hubble Space Telescope have uncovered surprising new clues about a hefty, rapidly aging star whose behavior has never been seen before in our Milky Way galaxy. In fact, the star is so weird that astronomers have nicknamed it “Nasty 1,” a play on its catalog name of NaSt1. The star may represent a brief transitory stage in the evolution of extremely massive stars. First discovered several decades ago, Nasty 1 was identified as a Wolf-Rayet star, a rapidly evolving star that is much more massive than our sun. The star loses its hydrogen-filled outer layers quickly, exposing its super-hot and extremely bright helium-burning core. But Nasty 1 doesn’t look like a typical Wolf-Rayet star. The astronomers using Hubble had expected to see twin lobes of gas flowing from opposite sides of the star, perhaps similar to those emanating from the massive star Eta Carinae, which is a Wolf-Rayet candidate. Instead, Hubble revealed a pancake-shaped disk of gas encircling the star. The vast disk is nearly 2 trillion miles wide, and may have formed from an unseen companion star that snacked on the outer envelope of the newly formed Wolf-Rayet. Based on current estimates, the nebula surrounding the stars is just a few thousand years old, and as close as 3,000 light-years from Earth. Credits: NASA/Hubble

Long-term changes and spatio-temporal variability of the growing season temperature in Europe during the last Millennium

NASA Astrophysics Data System (ADS)

Guiot, Joel; Corona, Christophe

2010-05-01

A gridded reconstruction of April to September temperature was produced for Europe based on tree-rings, documentaries, pollen and ice cores. The majority of the proxy series have an annual resolution. For a better inference of long-term climate variations, they were completed by number of low resolution data (decadal or more), mostly on pollen and ice-core data. An original spectral analogue method was devised to deal with this heterogeneous dataset, and especially to preserve the long-term variations and the variability of the temperature series. It is the condition is to make pertinent the comparison of the recent climate changes to a broader context of 1400 years. The reconstruction of the April-September temperature was validated with a Jack-knife technique, and it was also compared with other spatially gridded temperature reconstructions, literature data, and glacier advance and retreat curves. We also attempted to relate the spatial distribution of European temperature anomalies to known solar and volcanic forcings. We found that (1) our results are sound back to A.D. 750; (2) conditions during the last decade have exceeded all those known during the last millennium; (3) before the 20th century, cold periods can partly be explained by low solar activity and/or high volcanic activity and that Medieval Warm Period (MWP) is consistent with a high solar activity; (4) during the 20th century, however only anthropogenic forcing can explain the exceptionally high temperature rise; (5) based on an analysis of the distribution of extreme temperatures, the maximum event of the Medieval Period (1.1°C higher than the 1960-1990 reference period) had a return period of more than 1000 years, but this recently fell to less than 26 years; (6) all decades before AD 1350 were warm on average but relatively heterogeneous, while the last decade was homogeneously warmer. These results support the fact that we are facing an unprecedented changing climate in Europe unlike any known in the last 1000 years, as pointed out previously. The new result is that this anthropogenic change is characterised by spatial homogeneity and changes as well in average temperatures than in distribution of extreme events, while natural climate forcings induce warm periods with heterogeneous spatial patterns and less frequent extreme events. This study demonstrates that recent changes in temperature differ substantially from temperature changes reconstructed in the past and are well in excess of normal variations experienced in previous centuries and caused by natural forcings.

Partially covered versus uncovered self-expandable nitinol stents with anti-migration properties for the palliation of malignant distal biliary obstruction: A randomized controlled trial.

PubMed

Yang, Min Jae; Kim, Jin Hong; Yoo, Byung Moo; Hwang, Jae Chul; Yoo, Jun Hwan; Lee, Ki Seong; Kang, Joon Koo; Kim, Soon Sun; Lim, Sun Gyo; Shin, Sung Jae; Cheong, Jae Youn; Lee, Kee Myung; Lee, Kwang Jae; Cho, Sung Won

2015-01-01

Covered self-expandable metal stents (SEMSs) are increasingly used as alternatives to uncovered SEMSs for the palliation of inoperable malignant distal biliary obstruction to counteract tumor ingrowth. We aimed to compare the outcomes of partially covered and uncovered SEMSs with identical mesh structures and anti-migration properties, such as low axial force and flared ends. One hundred and three patients who were diagnosed with inoperable malignant distal biliary obstruction between January 2006 and August 2013 were randomly assigned to either the partially covered (n = 51) or uncovered (n = 52) SEMS group. There were no significant differences in the cumulative stent patency, overall patient survival, stent dysfunction-free survival and overall adverse events, including pancreatitis and cholecystitis, between the two groups. Compared to the uncovered group, stent migration (5.9% vs. 0%, p = 0.118) and tumor overgrowth (7.8% vs. 1.9%, p = 0.205) were non-significantly more frequent in the partially covered group, whereas tumor ingrowth showed a significantly higher incidence in the uncovered group (5.9% vs. 19.2%, p = 0.041). Stent migration in the partially covered group occurred only in patients with short stenosis of the utmost distal bile duct (two in ampullary cancer, one in bile duct cancer), and did not occur in any patients with pancreatic cancer. For the palliation of malignant distal biliary obstruction, endoscopic placement of partially covered SEMSs with anti-migration designs and identical mesh structures to uncovered SEMSs failed to prolong cumulative stent patency or reduce stent migration.

Whole-Exome Sequencing in Two Extreme Phenotypes of Response to VEGF-Targeted Therapies in Patients With Metastatic Clear Cell Renal Cell Carcinoma.

PubMed

Fay, Andre P; de Velasco, Guillermo; Ho, Thai H; Van Allen, Eliezer M; Murray, Bradley; Albiges, Laurence; Signoretti, Sabina; Hakimi, A Ari; Stanton, Melissa L; Bellmunt, Joaquim; McDermott, David F; Atkins, Michael B; Garraway, Levi A; Kwiatkowski, David J; Choueiri, Toni K

2016-07-01

Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)-targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT. Copyright © 2016 by the National Comprehensive Cancer Network.

Towards prediction of heatwaves based on the complementary relationship between actual and potential evaporation - energy partitioning and hydrologic attributes

NASA Astrophysics Data System (ADS)

Or, D.; Aminzadeh, M.; Roderick, M. L.

2017-12-01

Prediction of extreme climate events such as heatwaves that are characterized by prolonged periods of high air temperatures (accompanied by low precipitation and high radiation) provides an opportunity to potentially mitigate the associated environmental, social and economic impacts. Vegetation may respond to these extreme conditions by reducing evaporative flux either due to soil water depletion or inability to meet the atmospheric evaporative demand (high canopy resistance). We implement a newly generalized Complementary Relationship (CR) for spatially heterogeneous land surfaces to predict the actual evaporation from drying landscapes covered by different vegetation types (i.e., grassland and forest). A strong correlation between air temperature and sensible heat flux anomalies identified from FLUXNET network data suggests that abrupt changes in sensible heat flux above climatological means can serve as indicators for predicting the onset of a heatwave. We thus capitalize on the inherent coupling between evaporative and sensible heat fluxes linked to moisture availability within the CR framework to predict rapid increase in regional sensible heat flux associated with soil drying (low precipitation) or with extreme evaporative demand (high radiation) while soil moisture is not limiting. The proposed approach evaluated using FLUXNET datasets provides an energy constraint framework based on the CR concept to obtain new insights into the onset of heatwaves and climate extremes such as regional droughts.

Extreme Landfalling Atmospheric River Events in Arizona: Possible Future Changes

NASA Astrophysics Data System (ADS)

Singh, I.; Dominguez, F.

2016-12-01

Changing climate could impact the frequency and intensity of extreme atmospheric river events. This can have important consequences for regions like the Southwestern United Sates that rely upon AR-related precipitation for meeting their water demand and are prone to AR-related flooding. This study investigates the effects of climate change on extreme AR events in the Salt and Verde river basins in Central Arizona using a pseudo global warming method (PGW). First, the five most extreme events that affected the region were selected. High-resolution control simulations of these events using the Weather Research and Forecasting model realistically captured the magnitude and spatial distribution of precipitation. Subsequently, following the PGW approach, the WRF initial and lateral boundary conditions were perturbed. The perturbation signals were obtained from an ensemble of 9 General Circulation Models for two warming scenarios - Representative Concentration Pathway (RCP) 4.5 and RCP8.5. Several simulations were conducted changing the temperature and relative humidity fields. PGW simulations reveal that while the overall dynamics of the storms did not change significantly, there was marked strengthening of associated Integrated Vertical Transport (IVT) plumes. There was a general increase in the precipitation over the basins due to increased moisture availability, but heterogeneous spatial changes. Additionally, no significant changes in the strength of the pre-cold frontal low-level jet in the future simulations were observed.

Phylogenetic relationships and taxonomic position of Chlorella-like isolates from low pH environments (pH < 3.0)

PubMed Central

Huss, Volker AR; Ciniglia, Claudia; Cennamo, Paola; Cozzolino, Salvatore; Pinto, Gabriele; Pollio, Antonino

2002-01-01

Background Little is known about phytoplankton communities inhabiting low pH environments such as volcanic and geothermal sites or acidic waters. Only specialised organisms are able to tolerate such extreme conditions. There is, thus, low species diversity. We have characterised the previously isolated acid tolerant Chlorella-like microalgae Viridiella fridericiana and Chlorella protothecoides var. acidicola by microscopical and biomolecular methods in order to assess their phylogenetic relationships. Results Both isolates belong to the trebouxiophycean lineage of chlorophytes. 18S and ITS1 sequence data clearly confirm that Viridiella fridericiana constitutes a new genus apart from the morphologically similar and likewise acid tolerant microalga Chlorella saccharophila. Chlorella protothecoides var. acidicola on the other hand is not a variety of Chlorella protothecoides but falls within a heterogeneous cluster consisting of Nannochloris, "Chlorella" spec. Yanaqocha, and Koliella, and is most closely related to algae which were also isolated from extreme environments. Conclusions The distribution of acid tolerant strains in the 18S rRNA tree shows that acquisition of acid tolerance was unlikely a monophyletic event in green microalgae. We propose that different strains have independently adapted to extreme environments. Some of them have spread worldwide and were able to colonise other extreme habitats. Considering the problems of successfully isolating acid tolerant strains, acidic soils could represent an unsuspected source of biological diversity with high potential for biotechnological utilisations. PMID:12194702

MO-F-CAMPUS-I-01: Accuracy of Radiologists Interpretation of Mammographic Breast Density

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vedantham, S; Shi, L; Karellas, A

2015-06-15

Purpose: Several commercial and non-commercial software and techniques are available for determining breast density from mammograms. However, where mandated by law the breast density information communicated to the subject/patient is based on radiologist’s interpretation of breast density from mammograms. Several studies have reported on the concordance among radiologists in interpreting mammographic breast density. In this work, we investigated the accuracy of radiologist’s interpretation of breast density. Methods: Volumetric breast density (VBD) determined from 134 unilateral dedicated breast CT scans from 134 subjects was considered the truth. An MQSA-qualified study radiologist with more than 20 years of breast imaging experience reviewedmore » the DICOM “for presentation” standard 2-view mammograms of the corresponding breasts and assigned BIRADS breast density categories. For statistical analysis, the breast density categories were dichotomized in two ways; fatty vs. dense breasts where “fatty” corresponds to BIRADS breast density categories A/B, and “dense” corresponds to BIRADS breast density categories C/D, and extremely dense vs. fatty to heterogeneously dense breasts, where extremely dense corresponds to BIRADS breast density category D and BIRADS breast density categories A through C were grouped as fatty to heterogeneously dense breasts. Logistic regression models (SAS 9.3) were used to determine the association between radiologist’s interpretation of breast density and VBD from breast CT, from which the area under the ROC (AUC) was determined. Results: Both logistic regression models were statistically significant (Likelihood Ratio test, p<0.0001). The accuracy (AUC) of the study radiologist for classification of fatty vs. dense breasts was 88.4% (95% CI: 83–94%) and for classification of extremely dense breast was 94.3% (95% CI: 90–98%). Conclusion: The accuracy of the radiologist in classifying dense and extremely dense breasts is high. Considering the variability in VBD estimates from commercial software, the breast density information communicated to the patient should be based on radiologist’s interpretation. This work was supported in part by NIH R21 CA176470 and R21 CA134128. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or NCI.« less

Volatile element chemistry in the solar nebula - Na, K, F, Cl, Br, and P

NASA Technical Reports Server (NTRS)

Fegley, B., Jr.; Lewis, J. S.

1980-01-01

The results of the most extensive set to date of thermodynamic calculations on the equilibrium chemistry of several hundred compounds of the elements Na, K, F, Cl, Br, and P in a solar composition system are reported. Two extreme models of accretion are investigated. In one extreme complete chemical equilibrium between condensates and gases is maintained because the time scale for accretion is long compared to the time scale for cooling or dissipation of the nebula. Condensates formed in this homogeneous accretion model include several phases such as whitlockite, alkali feldspars, and apatite minerals which are found in chondrites. In the other extreme complete isolation of newly formed condensates from prior condensates and gases occurs due to a time scale for accretion that is short relative to the time required for nebular cooling or dissipation. The condensates produced in this heterogeneous accretion model include alkali sulfides, ammonium halides, and ammonium phosphates. None of these phases are found in chondrites. Available observations of the Na, K, F, Cl, Br, and P elemental abundances in the terrestrial planets are found to be compatible with the predictions of the homogeneous accretion model.

A Highly Stable Porphyrinic Zirconium Metal–Organic Framework with shp-a Topology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Dawei; Gu, Zhi-Yuan; Chen, Ying-Pin

2014-12-24

Through a kinetically controlled synthetic process, we synthesized PCN-223, a new porphyrinic Zr-MOF constructed from the newly reported hexagonal prismatic 12-connected Zr6 cluster through an unusual disordered arrangement, giving rise to the first example of the shp-a network in MOFs. With its extremely high connectivity, PCN-223 shows high stability in aqueous solutions with a wide range of pH. Cationic PCN-223(Fe) formed by postsynthetic treatment is an excellent recyclable heterogeneous catalyst for the hetero-Diels–Alder reaction.

What is new in systemic lupus erythematosus.

PubMed

Rúa-Figueroa Fernández de Larrinoa, Iñigo

2015-01-01

Systemic lupus erythematosus is a heterogeneous rheumatic systemic disease with extremely varied clinical manifestations and a diverse pathogenesis, as illustrated in this review on the most relevant new knowledge related to the disease. Topics such as anemia, pathogenesis, cardiovascular risk assessment, antiphospholipid syndrome, prediction of damage and recent advances in treatment, including tolerogenic and biological agents, are discussed. Relevant contributions regarding classical therapies such as corticosteroid and antimalarials and their optimal use, as well as the roll of vitamin D, are also referred. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Annealing effects in plated-wire memory elements. II - Recrystallization in Permalloy films.

NASA Technical Reports Server (NTRS)

Marquardt, S. J.; Kench, J. R.

1971-01-01

Results of grain-size measurements in Permalloy platings suggest that recrystallization is possible at temperatures as low as 200 C, but that it is an extremely heterogeneous process. No worthwhile correlation was found to exist between observed grain size and magnetic dispersion in samples aged in the temperature range from 180 to 230 C. It is suggested that the magnetic aging which occurs under these conditions may be due to some other diffusion-controlled process than recrystallization; a process such as chemical homogenization is tentatively preferred.

How Historical Information Can Improve Extreme Value Analysis of Coastal Water Levels

NASA Astrophysics Data System (ADS)

Le Cozannet, G.; Bulteau, T.; Idier, D.; Lambert, J.; Garcin, M.

2016-12-01

The knowledge of extreme coastal water levels is useful for coastal flooding studies or the design of coastal defences. While deriving such extremes with standard analyses using tide gauge measurements, one often needs to deal with limited effective duration of observation which can result in large statistical uncertainties. This is even truer when one faces outliers, those particularly extreme values distant from the others. In a recent work (Bulteau et al., 2015), we investigated how historical information of past events reported in archives can reduce statistical uncertainties and relativize such outlying observations. We adapted a Bayesian Markov Chain Monte Carlo method, initially developed in the hydrology field (Reis and Stedinger, 2005), to the specific case of coastal water levels. We applied this method to the site of La Rochelle (France), where the storm Xynthia in 2010 generated a water level considered so far as an outlier. Based on 30 years of tide gauge measurements and 8 historical events since 1890, the results showed a significant decrease in statistical uncertainties on return levels when historical information is used. Also, Xynthia's water level no longer appeared as an outlier and we could have reasonably predicted the annual exceedance probability of that level beforehand (predictive probability for 2010 based on data until the end of 2009 of the same order of magnitude as the standard estimative probability using data until the end of 2010). Such results illustrate the usefulness of historical information in extreme value analyses of coastal water levels, as well as the relevance of the proposed method to integrate heterogeneous data in such analyses.

Extreme heat reduces and shifts United States premium wine production in the 21st century

PubMed Central

White, M. A.; Diffenbaugh, N. S.; Jones, G. V.; Pal, J. S.; Giorgi, F.

2006-01-01

Premium wine production is limited to regions climatically conducive to growing grapes with balanced composition and varietal typicity. Three central climatic conditions are required: (i) adequate heat accumulation; (ii) low risk of severe frost damage; and (iii) the absence of extreme heat. Although wine production is possible in an extensive climatic range, the highest-quality wines require a delicate balance among these three conditions. Although historical and projected average temperature changes are known to influence global wine quality, the potential future response of wine-producing regions to spatially heterogeneous changes in extreme events is largely unknown. Here, by using a high-resolution regional climate model forced by the Intergovernmental Panel on Climate Change Special Report on Emission Scenarios A2 greenhouse gas emission scenario, we estimate that potential premium winegrape production area in the conterminous United States could decline by up to 81% by the late 21st century. While increases in heat accumulation will shift wine production to warmer climate varieties and/or lower-quality wines, and frost constraints will be reduced, increases in the frequency of extreme hot days (>35°C) in the growing season are projected to eliminate winegrape production in many areas of the United States. Furthermore, grape and wine production will likely be restricted to a narrow West Coast region and the Northwest and Northeast, areas currently facing challenges related to excess moisture. Our results not only imply large changes for the premium wine industry, but also highlight the importance of incorporating fine-scale processes and extreme events in climate-change impact studies. PMID:16840557

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis.

PubMed

Hamada, Tsuyoshi; Keum, NaNa; Nishihara, Reiko; Ogino, Shuji

2017-03-01

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.

Cardiac Autonomic Regulation in Autism and Fragile X Syndrome: A Review

PubMed Central

Klusek, Jessica; Roberts, Jane E.; Losh, Molly

2014-01-01

Despite the significance of efforts to understand the biological basis of autism, progress in this area has been hindered, in part, by the considerable heterogeneity in the disorder. Fragile X syndrome (FXS), a monogenic condition associated with high risk for autism, may pave the way for the dissection of biological heterogeneity within idiopathic autism. This paper adopts a cross-syndrome biomarker approach to evaluate potentially overlapping profiles of cardiac arousal dysregulation (and broader autonomic dysfunction) in autism and FXS. Approaches such as this, aimed at delineating shared mechanisms across genetic syndromes, hold great potential for improving diagnostic precision, promoting earlier identification, and uncovering key systems that can be targeted in pharmaceutical/behavioral interventions. Biomarker approaches may be vital to deconstructing complex psychiatric disorders, and are currently promoted as such by major research initiatives such as the NIMH Research Domain Criteria (RDoC). Evidence reviewed here supports physiological dysregulation in a subset of individuals with autism, as evidenced by patterns of hyperarousal and dampened parasympathetic vagal tone, which overlap with the well-documented physiological profile of FXS. Moreover, there is growing support for a link between aberrant cardiac activity and core deficits associated with autism, such as communication and social impairment. The delineation of physiological mechanisms common to autism and FXS could lend insight into relationships between genetic etiology and behavioral endstates, highlighting FMR1 as a potential candidate gene. Research gaps and potential pitfalls are discussed to inform timely, well-controlled biomarker research that will ultimately promote better diagnosis and treatment of autism and associated conditions. PMID:25420222

Evolution of Scaling Emergence in Large-Scale Spatial Epidemic Spreading

PubMed Central

Wang, Lin; Li, Xiang; Zhang, Yi-Qing; Zhang, Yan; Zhang, Kan

2011-01-01

Background Zipf's law and Heaps' law are two representatives of the scaling concepts, which play a significant role in the study of complexity science. The coexistence of the Zipf's law and the Heaps' law motivates different understandings on the dependence between these two scalings, which has still hardly been clarified. Methodology/Principal Findings In this article, we observe an evolution process of the scalings: the Zipf's law and the Heaps' law are naturally shaped to coexist at the initial time, while the crossover comes with the emergence of their inconsistency at the larger time before reaching a stable state, where the Heaps' law still exists with the disappearance of strict Zipf's law. Such findings are illustrated with a scenario of large-scale spatial epidemic spreading, and the empirical results of pandemic disease support a universal analysis of the relation between the two laws regardless of the biological details of disease. Employing the United States domestic air transportation and demographic data to construct a metapopulation model for simulating the pandemic spread at the U.S. country level, we uncover that the broad heterogeneity of the infrastructure plays a key role in the evolution of scaling emergence. Conclusions/Significance The analyses of large-scale spatial epidemic spreading help understand the temporal evolution of scalings, indicating the coexistence of the Zipf's law and the Heaps' law depends on the collective dynamics of epidemic processes, and the heterogeneity of epidemic spread indicates the significance of performing targeted containment strategies at the early time of a pandemic disease. PMID:21747932

Utilization of machine learning for prediction of post-traumatic stress: a re-examination of cortisol in the prediction and pathways to non-remitting PTSD

PubMed Central

Galatzer-Levy, I R; Ma, S; Statnikov, A; Yehuda, R; Shalev, A Y

2017-01-01

To date, studies of biological risk factors have revealed inconsistent relationships with subsequent post-traumatic stress disorder (PTSD). The inconsistent signal may reflect the use of data analytic tools that are ill equipped for modeling the complex interactions between biological and environmental factors that underlay post-traumatic psychopathology. Further, using symptom-based diagnostic status as the group outcome overlooks the inherent heterogeneity of PTSD, potentially contributing to failures to replicate. To examine the potential yield of novel analytic tools, we reanalyzed data from a large longitudinal study of individuals identified following trauma in the general emergency room (ER) that failed to find a linear association between cortisol response to traumatic events and subsequent PTSD. First, latent growth mixture modeling empirically identified trajectories of post-traumatic symptoms, which then were used as the study outcome. Next, support vector machines with feature selection identified sets of features with stable predictive accuracy and built robust classifiers of trajectory membership (area under the receiver operator characteristic curve (AUC)=0.82 (95% confidence interval (CI)=0.80–0.85)) that combined clinical, neuroendocrine, psychophysiological and demographic information. Finally, graph induction algorithms revealed a unique path from childhood trauma via lower cortisol during ER admission, to non-remitting PTSD. Traditional general linear modeling methods then confirmed the newly revealed association, thereby delineating a specific target population for early endocrine interventions. Advanced computational approaches offer innovative ways for uncovering clinically significant, non-shared biological signals in heterogeneous samples. PMID:28323285

Utilization of machine learning for prediction of post-traumatic stress: a re-examination of cortisol in the prediction and pathways to non-remitting PTSD.

PubMed

Galatzer-Levy, I R; Ma, S; Statnikov, A; Yehuda, R; Shalev, A Y

2017-03-21

To date, studies of biological risk factors have revealed inconsistent relationships with subsequent post-traumatic stress disorder (PTSD). The inconsistent signal may reflect the use of data analytic tools that are ill equipped for modeling the complex interactions between biological and environmental factors that underlay post-traumatic psychopathology. Further, using symptom-based diagnostic status as the group outcome overlooks the inherent heterogeneity of PTSD, potentially contributing to failures to replicate. To examine the potential yield of novel analytic tools, we reanalyzed data from a large longitudinal study of individuals identified following trauma in the general emergency room (ER) that failed to find a linear association between cortisol response to traumatic events and subsequent PTSD. First, latent growth mixture modeling empirically identified trajectories of post-traumatic symptoms, which then were used as the study outcome. Next, support vector machines with feature selection identified sets of features with stable predictive accuracy and built robust classifiers of trajectory membership (area under the receiver operator characteristic curve (AUC)=0.82 (95% confidence interval (CI)=0.80-0.85)) that combined clinical, neuroendocrine, psychophysiological and demographic information. Finally, graph induction algorithms revealed a unique path from childhood trauma via lower cortisol during ER admission, to non-remitting PTSD. Traditional general linear modeling methods then confirmed the newly revealed association, thereby delineating a specific target population for early endocrine interventions. Advanced computational approaches offer innovative ways for uncovering clinically significant, non-shared biological signals in heterogeneous samples.

Detecting Adaptation in Protein-Coding Genes Using a Bayesian Site-Heterogeneous Mutation-Selection Codon Substitution Model.

PubMed

Rodrigue, Nicolas; Lartillot, Nicolas

2017-01-01

Codon substitution models have traditionally attempted to uncover signatures of adaptation within protein-coding genes by contrasting the rates of synonymous and non-synonymous substitutions. Another modeling approach, known as the mutation-selection framework, attempts to explicitly account for selective patterns at the amino acid level, with some approaches allowing for heterogeneity in these patterns across codon sites. Under such a model, substitutions at a given position occur at the neutral or nearly neutral rate when they are synonymous, or when they correspond to replacements between amino acids of similar fitness; substitutions from high to low (low to high) fitness amino acids have comparatively low (high) rates. Here, we study the use of such a mutation-selection framework as a null model for the detection of adaptation. Following previous works in this direction, we include a deviation parameter that has the effect of capturing the surplus, or deficit, in non-synonymous rates, relative to what would be expected under a mutation-selection modeling framework that includes a Dirichlet process approach to account for across-codon-site variation in amino acid fitness profiles. We use simulations, along with a few real data sets, to study the behavior of the approach, and find it to have good power with a low false-positive rate. Altogether, we emphasize the potential of recent mutation-selection models in the detection of adaptation, calling for further model refinements as well as large-scale applications. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis

PubMed Central

Hamada, Tsuyoshi; Keum, NaNa; Nishihara, Reiko; Ogino, Shuji

2016-01-01

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on “the unique disease principle,” the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine. PMID:27738762

Multidimensional Single-Cell Analysis of BCR Signaling Reveals Proximal Activation Defect As a Hallmark of Chronic Lymphocytic Leukemia B Cells

PubMed Central

Palomba, M. Lia; Piersanti, Kelly; Ziegler, Carly G. K.; Decker, Hugo; Cotari, Jesse W.; Bantilan, Kurt; Rijo, Ivelise; Gardner, Jeff R.; Heaney, Mark; Bemis, Debra; Balderas, Robert; Malek, Sami N.; Seymour, Erlene; Zelenetz, Andrew D.

2014-01-01

Purpose Chronic Lymphocytic Leukemia (CLL) is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation. Experimental Design We developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR). Results from multidimensional modeling were validated using an independent test cohort of 38 patients. Results We identified a dynamic and variable imbalance between proximal (pSYK, pBTK) and distal (pPLCγ2, pBLNK, ppERK) phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness. Conclusion Single-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets. PMID:24489640

The National Integrated Heat Health Information System (NIHHIS) as a Learning System for Extreme Heat: Evolving Future Resilience from Present Climate Extremes

NASA Astrophysics Data System (ADS)

Jones, H.; Trtanj, J.; Pulwarty, R. S.; Higgins, W.

2016-12-01

There is presently no consensus indicator for the effect of extreme heat on human health. At the early warning timescale, a variety of approaches to setting temperature thresholds (minimum, maximum, time-lagged) or more complex approaches (Heat Index, Thermal Comfort, etc...) for issuing alerts and warnings have been recommended by literature and implemented, leading to much heterogeneity. At longer timescales, efforts have been made to quantify potential future health outcomes using climate projections, but nonstationarity of the climate system, economy, and demography may invalidate many of the assumptions which were necessarily made in these studies. Furthermore, in our pursuit of developing the best models and indicators to represent the impacts of climate extremes, perhaps we have not paid enough attention to what makes them policy-relevant, responsive to changing assumptions, and targeted at elements that can actually be predicted. In response to this concern, a comprehensive approach to improving the impactfulness of these indicators is underway as part of the National Integrated Heat Health Information System (NIHHIS), which was initiated by NOAA and CDC, but has grown to include many other federal agency and non-governmental partners. NIHHIS is a framework that integrates what we know about extreme heat and health outcomes within a learning system - simultaneously informing early warning and long-term risk reduction prior to, during, and while recovering from extreme heat events. NIHHIS develops impactful evolutionary responses to climate extremes. Through ongoing regional engagements, we are applying the lessons of impact modeling studies to create learning systems in the Southwest, Northeast, Midwest, and soon other regions of the U.S. This session will provide a view of this process as it has been carried out in the Southwest region - focused on the transboundary (US-Mexico) region around El Paso, Texas, and the NIHHIS approach to indicators overall.

Application of fuzzy c-means clustering to PRTR chemicals uncovering their release and toxicity characteristics.

PubMed

Xue, Mianqiang; Zhou, Liang; Kojima, Naoya; Dos Muchangos, Leticia Sarmento; Machimura, Takashi; Tokai, Akihiro

2018-05-01

Increasing manufacture and usage of chemicals have not been matched by the increase in our understanding of their risks. Pollutant release and transfer register (PRTR) is becoming a popular measure for collecting chemical data and enhancing the public right to know. However, these data are usually in high dimensionality which restricts their wider use. The present study partitions Japanese PRTR chemicals into five fuzzy clusters by fuzzy c-mean clustering (FCM) to explore the implicit information. Each chemical with membership degrees belongs to each cluster. Cluster I features high releases from non-listed industries and the household sector and high environmental toxicity. Cluster II is characterized by high reported releases and transfers from 24 listed industries above the threshold, mutagenicity, and high environmental toxicity. Chemicals in cluster III have characteristics of high releases from non-listed industries and low toxicity. Cluster IV is characterized by high reported releases and transfers from 24 listed industries above the threshold and extremely high environmental toxicity. Cluster V is characterized by low releases yet mutagenicity and high carcinogenicity. Chemicals with the highest membership degree were identified as representatives for each cluster. For the highest membership degree, half of the chemicals have a value higher than 0.74. If we look at both the highest and the second highest membership degrees simultaneously, about 94% of the chemicals have a value higher than 0.5. FCM can serve as an approach to uncover the implicit information of highly complex chemical dataset, which subsequently supports the strategy development for efficient and effective chemical management. Copyright © 2017 Elsevier B.V. All rights reserved.

Vegetation anomalies caused by antecedent precipitation in most of the world

NASA Astrophysics Data System (ADS)

Papagiannopoulou, C.; Miralles, D. G.; Dorigo, W. A.; Verhoest, N. E. C.; Depoorter, M.; Waegeman, W.

2017-07-01

Quantifying environmental controls on vegetation is critical to predict the net effect of climate change on global ecosystems and the subsequent feedback on climate. Following a non-linear Granger causality framework based on a random forest predictive model, we exploit the current wealth of multi-decadal satellite data records to uncover the main drivers of monthly vegetation variability at the global scale. Results indicate that water availability is the most dominant factor driving vegetation globally: about 61% of the vegetated surface was primarily water-limited during 1981-2010. This included semiarid climates but also transitional ecoregions. Intra-annually, temperature controls Northern Hemisphere deciduous forests during the growing season, while antecedent precipitation largely dominates vegetation dynamics during the senescence period. The uncovered dependency of global vegetation on water availability is substantially larger than previously reported. This is owed to the ability of the framework to (1) disentangle the co-linearities between radiation/temperature and precipitation, and (2) quantify non-linear impacts of climate on vegetation. Our results reveal a prolonged effect of precipitation anomalies in dry regions: due to the long memory of soil moisture and the cumulative, non-linear, response of vegetation, water-limited regions show sensitivity to the values of precipitation occurring three months earlier. Meanwhile, the impacts of temperature and radiation anomalies are more immediate and dissipate shortly, pointing to a higher resilience of vegetation to these anomalies. Despite being infrequent by definition, hydro-climatic extremes are responsible for up to 10% of the vegetation variability during the 1981-2010 period in certain areas, particularly in water-limited ecosystems. Our approach is a first step towards a quantitative comparison of the resistance and resilience signature of different ecosystems, and can be used to benchmark Earth system models in their representations of past vegetation sensitivity to changes in climate.

Accurate detection of hierarchical communities in complex networks based on nonlinear dynamical evolution

NASA Astrophysics Data System (ADS)

Zhuo, Zhao; Cai, Shi-Min; Tang, Ming; Lai, Ying-Cheng

2018-04-01

One of the most challenging problems in network science is to accurately detect communities at distinct hierarchical scales. Most existing methods are based on structural analysis and manipulation, which are NP-hard. We articulate an alternative, dynamical evolution-based approach to the problem. The basic principle is to computationally implement a nonlinear dynamical process on all nodes in the network with a general coupling scheme, creating a networked dynamical system. Under a proper system setting and with an adjustable control parameter, the community structure of the network would "come out" or emerge naturally from the dynamical evolution of the system. As the control parameter is systematically varied, the community hierarchies at different scales can be revealed. As a concrete example of this general principle, we exploit clustered synchronization as a dynamical mechanism through which the hierarchical community structure can be uncovered. In particular, for quite arbitrary choices of the nonlinear nodal dynamics and coupling scheme, decreasing the coupling parameter from the global synchronization regime, in which the dynamical states of all nodes are perfectly synchronized, can lead to a weaker type of synchronization organized as clusters. We demonstrate the existence of optimal choices of the coupling parameter for which the synchronization clusters encode accurate information about the hierarchical community structure of the network. We test and validate our method using a standard class of benchmark modular networks with two distinct hierarchies of communities and a number of empirical networks arising from the real world. Our method is computationally extremely efficient, eliminating completely the NP-hard difficulty associated with previous methods. The basic principle of exploiting dynamical evolution to uncover hidden community organizations at different scales represents a "game-change" type of approach to addressing the problem of community detection in complex networks.

Exploring local perceptions and attributions of 'extreme' wildfire impacts in Rural Montana

NASA Astrophysics Data System (ADS)

Carroll, M.; Paveglio, T.; Kallman, D.

2013-12-01

To date there have been few systematic efforts to uncover the criteria that local stakeholders use to perceive of and make judgments about the severity of wildfire impacts to the social-ecological systems they are a part of. The study presented here sought to uncover expanded understandings of perceived social and ecological impacts from a wildfire in rural Montana and the underlying causes for those perceived impacts. Such efforts could lead to more comprehensive social impact assessment concerning wildfires or other hazards and help better understand how local perceptions might influence residents' ongoing attitudes toward fire risk or mitigation efforts. The study presented here explored local perceptions of impact from the 2012 Dahl fire near Roundup, MT. The Dahl Fire burned 73 permanent structures, 150 outbuilding and 22,000 acres of predominantly private lands in the rural Bull Mountains. Members of the project team interviewed approximately 50 stakeholders impacted by or involved in the management for the Dahl Fire. Interviews took place in the summer of 2013 and included a variety of residents, emergency personnel, firefighters, local community officials and land management professionals. Results suggest that residents considered the Dahl fire especially impactful given the number of private residences and structures that were burned and the number of people displaced or disrupted by the event (either directly, through efforts to help those affected, or through indirect impacts to community function). The extremity of the firefighting conditions (e.g. wind, relative humidity, terrain), the rapidity of fire spread through populated areas and the damages sustained given previous fires in the area all surprised stakeholders and contributed to their perceptions of impact severity. Conflicts over access to properties during and immediately following the fire, and the variable perception that personal wildfire mitigations did little to reduce damages from the fire also contributed to perceptions about the level of wildfire impact. Many respondents felt that impacts from the Dahl Fire were the result of historic development patterns that allowed for mid-sized, rural subdivisions in heavily forested draws and along rough roads. Residents in these areas often moved to the Bull Mountains for privacy and to exercise significant property rights. Other residents felt the fire was not attacked quickly enough. Resident response to the impacts was almost universally perceived as well organized and effective. It was predicated on the collaborative capacity of local groups, community ties and experience with historic floods the year prior to the fire. Unexpected longer-term impacts such as high levels of erosion and flash-flooding have kept the fire in the minds of residents and contributed to their perceptions of impact. Respondents (including those with homes that burned) indicated that a significant portion of those whose property was damaged did not intend to return or rebuild. This is somewhat unique in response to wildfires and should be explored in future fires perceived by locals as extreme in order to test for emerging trends.

Comparison of Covered Versus Uncovered Stents for Benign Superior Vena Cava (SVC) Obstruction.

PubMed

Haddad, Mustafa M; Simmons, Benjamin; McPhail, Ian R; Kalra, Manju; Neisen, Melissa J; Johnson, Matthew P; Stockland, Andrew H; Andrews, James C; Misra, Sanjay; Bjarnason, Haraldur

2018-05-01

To identify whether long-term symptom relief and stent patency vary with the use of covered versus uncovered stents for the treatment of benign SVC obstruction. We retrospectively identified all patients with benign SVC syndrome treated to stent placement between January 2003 and December 2015 (n = 59). Only cases with both clinical and imaging follow-up were included (n = 47). In 33 (70%) of the patients, the obstruction was due to a central line or pacemaker wires, and in 14 (30%), the cause was fibrosing mediastinitis. Covered stents were placed in 17 (36%) of the patients, and 30 (64%) patients had an uncovered stent. Clinical and treatment outcomes, complications, and the percent stenosis of each stent were evaluated. Technical success was achieved in all cases at first attempt. Average clinical and imaging follow-up in years was 2.7 (range 0.1-11.1) (covered) and 1.7 (range 0.2-10.5) (uncovered), respectively. There was a significant difference (p = 0.044) in the number of patients who reported a return of symptoms between the covered (5/17 or 29.4%) and uncovered (18/30 or 60%) groups. There was also a significant difference (p = < 0.001) in the mean percent stenosis after stent placement between the covered [17.9% (range 0-100) ± 26.2] and uncovered [48.3% (range 6.8-100) ± 33.5] groups. No significant difference (p = 0.227) was found in the time (days) between the date of the procedure and the date of clinical follow-up where a return of symptoms was reported [covered: 426.6 (range 28-1554) ± 633.9 and uncovered 778.1 (range 23-3851) ± 1066.8]. One patient in the uncovered group had non-endovascular surgical intervention (innominate to right atrial bypass), while none in the covered group required surgical intervention. One major complication (SIR grade C) occurred that consisted of a pericardial hemorrhagic effusion after angioplasty that required covered stent placement. There were no procedure-related deaths. Both covered and uncovered stents can be used for treating benign SVC syndrome. Covered stents, however, may be a more effective option at providing symptom relief and maintaining stent patency if validated by further studies.

On the relevance of the methane oxidation cycle to ozone hole chemistry

NASA Technical Reports Server (NTRS)

Mueller, Rolf; Crutzen, Paul J.

1994-01-01

High concentrations of active chlorine are clearly responsible for the observed ozone depletion during the Antarctic polar spring. However, the mechanism behind the activation of chlorine from the reservoirs species HCl and ClONO2 and the maintenance of extremely high levels of active chlorine after polar sunrise is less well understood. Here, we focus on the influence of the methane oxidation cycle on 'ozone hole' chemistry through its effect on HOx and ClOx radicals. We demonstrate the great potential importance of the heterogeneous reaction HCl + HOCl yields Cl2 + H2O and the gasphase reaction ClO + CH3O2 yields ClOO + CH3O under sunlight conditions in polar spring. Under these conditions, the heterogeneous reaction is the main sink for HOx radicals. Through this channel, the HCl reservoir may be almost completely depleted. The gas phase reaction may control the levels of the CH3O2 radical, provided that high levels of ClO exist. Otherwise this radical initiates a sequence of reactions leading to a considerable loss of active chlorine. Moreover, the production of HOx radicals is reduced, and thereby the efficiency of the heterogeneous reaction limited. The two reactions together may accomplish the complete conversion of HCl into active chlorine, thereby leading to a rapid destruction of ozone.