ANALYSIS AND VISUALIZATION OF FLOW FIELDS USING INFORMATION-THEORETIC TECHNIQUES AND GRAPH-BASED REPRESENTATIONS

Three-dimensional flow visualization plays an essential role in many areas of science and engineering, such as aero- and hydro-dynamical systems which dominate various physical and natural phenomena. For popular methods such as the streamline visualization to be effective, they should capture the underlying flow features while facilitating user observation and understanding of the flow field in a clear manner. My research mainly focuses on the analysis and visualization of flow fields using various techniques, e.g. information-theoretic techniques and graph-based representations. Since the streamline visualization is a popular technique in flow field visualization, how to select good streamlines to capture flow patterns and how to pick good viewpoints to observe flow fields become critical. We treat streamline selection and viewpoint selection as symmetric problems and solve them simultaneously using the dual information channel [81]. To the best of my knowledge, this is the first attempt in flow visualization to combine these two selection problems in a unified approach. This work selects streamline in a view-independent manner and the selected streamlines will not change for all viewpoints. My another work [56] uses an information-theoretic approach to evaluate the importance of each streamline under various sample viewpoints and presents a solution for view-dependent streamline selection that guarantees coherent streamline update when the view changes gradually. When projecting 3D streamlines to 2D images for viewing, occlusion and clutter become inevitable. To address this challenge, we design FlowGraph [57, 58], a novel compound graph representation that organizes field line clusters and spatiotemporal regions hierarchically for occlusion-free and controllable visual exploration. We enable observation and exploration of the relationships among field line clusters, spatiotemporal regions and their interconnection in the transformed space. Most viewpoint selection methods only consider the external viewpoints outside of the flow field. This will not convey a clear observation when the flow field is clutter on the boundary side. Therefore, we propose a new way to explore flow fields by selecting several internal viewpoints around the flow features inside of the flow field and then generating a B-Spline curve path traversing these viewpoints to provide users with closeup views of the flow field for detailed observation of hidden or occluded internal flow features [54]. This work is also extended to deal with unsteady flow fields. Besides flow field visualization, some other topics relevant to visualization also attract my attention. In iGraph [31], we leverage a distributed system along with a tiled display wall to provide users with high-resolution visual analytics of big image and text collections in real time. Developing pedagogical visualization tools forms my other research focus. Since most cryptography algorithms use sophisticated mathematics, it is difficult for beginners to understand both what the algorithm does and how the algorithm does that. Therefore, we develop a set of visualization tools to provide users with an intuitive way to learn and understand these algorithms.

ENVISIONING QUEER THROUGH DIGITAL MEDIA: DEVELOPING A COMMUNITY-BASED WORKSHOP IN MEDIA ANALYSIS FOR LGBTQIA+ YOUTH

This project consists of a proposed curriculum for a semester-long, community-based workshop for LGBTQIA+ (lesbian, gay, bisexual, trans*, queer or questioning, intersex, asexual or ally, "+" indicating other identifications that deviate from heterosexual) youth ages 16-18. The workshop focuses on an exploration of LGBTQIA+ identity and community through discussion and collaborative rhetorical analysis of visual and social media. Informed by queer theory and history, studies on youth work, and visual media studies and incorporating rhetorical criticism as well as liberatory pedagogy and community literacy practices, the participation-based design of the workshop seeks to involve participants in selection of media texts, active analytical viewership, and multimodal response. The workshop is designed to engage participants in reflection on questions of individual and collective responsibility and agency as members and allies of various communities. The goal of the workshop is to strengthen participants' abilities to analyze the complex ways in which television, film, and social media influence their own and others’ perceptions of issues surrounding queer identities. As part of the reflective process, participants are challenged to consider how they can in turn actively and collaboratively respond to and potentially help to shape these perceptions. My project report details the theoretical framework, pedagogical rationale, methods of text selection and critical analysis, and guidelines for conduct that inform and structure the workshop.

Selection on floral traits through male fertility in a natural plant population

Most studies on selection in plants estimate female fitness components and neglect male mating success, although the latter might also be fundamental to understand adaptive evolution. Information from molecular genetic markers can be used to assess determinants of male mating success through parentage analyses. We estimated paternal selection gradients on floral traits in a large natural population of the herb Mimulus guttatus using a paternity probability model and maximum likelihood methods. This analysis revealed more significant selection gradients than a previous analysis based on regression of estimated male fertilities on floral traits. There were differences between results of univariate and multivariate analyses most likely due to the underlying covariance structure of the traits. Multivariate analysis, which corrects for the covariance structure of the traits, indicated that male mating success declined with distance from and depended on the direction to the mother plants. Moreover, there was directional selection for plants with fewer open flowers which have smaller corollas, a smaller anther-stigma separation, more red dots on the corolla and a larger fluctuating asymmetry therein. For most of these traits, however, there was also stabilizing selection indicating that there are intermediate optima for these traits. The large number of significant selection gradients in this study shows that even in relatively large natural populations where not all males can be sampled, it is possible to detect significant paternal selection gradients, and that such studies can give us valuable information required to better understand adaptive plant evolution.

Erythropoietin or Darbepoetin for patients with cancer--meta-analysis based on individual patient data

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality. OBJECTIVES: Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients. SEARCH STRATEGY: We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials. SELECTION CRITERIA: We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy. DATA COLLECTION AND ANALYSIS: We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint. MAIN RESULTS: A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42). AUTHORS' CONCLUSIONS: ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.

Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice

BACKGROUND: Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in individuals with mental retardation and congenital abnormality. Copy number variations (CNVs) are now readily detectable using a variety of platforms and a major challenge is the distinction of pathogenic from ubiquitous, benign polymorphic CNVs. The aim of this study was to investigate replacement of time consuming, locus specific testing for specific microdeletion and microduplication syndromes with microarray analysis, which theoretically should detect all known syndromes with CNV aetiologies as well as new ones. METHODS: Genome wide copy number analysis was performed on 117 patients using Affymetrix 250K microarrays. RESULTS: 434 CNVs (195 losses and 239 gains) were found, including 18 pathogenic CNVs and 9 identified as "potentially pathogenic". Almost all pathogenic CNVs were larger than 500 kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity larger than 5 Mb were found in 5 patients. CONCLUSIONS: Genome microarray analysis has improved diagnostic success in this group of patients. Several examples of recently discovered "new syndromes" were found suggesting they are more common than previously suspected and collectively are likely to be a major cause of mental retardation. The findings have several implications for clinical practice. The study revealed the potential to make genetic diagnoses that were not evident in the clinical presentation, with implications for pretest counselling and the consent process. The importance of contributing novel CNVs to high quality databases for genotype-phenotype analysis and review of guidelines for selection of individuals for microarray analysis is emphasised.

Is body weight the most appropriate criterion to select patients eligible for low-dose pulmonary CT angiography? Analysis of objective and subjective image quality at 80 kVp in 100 patients

The objective of this retrospective study was to assess image quality with pulmonary CT angiography (CTA) using 80 kVp and to find anthropomorphic parameters other than body weight (BW) to serve as selection criteria for low-dose CTA. Attenuation in the pulmonary arteries, anteroposterior and lateral diameters, cross-sectional area and soft-tissue thickness of the chest were measured in 100 consecutive patients weighing less than 100 kg with 80 kVp pulmonary CTA. Body surface area (BSA) and contrast-to-noise ratios (CNR) were calculated. Three radiologists analyzed arterial enhancement, noise, and image quality. Image parameters between patients grouped by BW (group 1: 0-50 kg; groups 2-6: 51-100 kg, decadally increasing) were compared. CNR was higher in patients weighing less than 60 kg than in the BW groups 71-99 kg (P between 0.025 and <0.001). Subjective ranking of enhancement (P = 0.165-0.605), noise (P = 0.063), and image quality (P = 0.079) did not differ significantly across all patient groups. CNR correlated moderately strongly with weight (R = -0.585), BSA (R = -0.582), cross-sectional area (R = -0.544), and anteroposterior diameter of the chest (R = -0.457; P < 0.001 all parameters). We conclude that 80 kVp pulmonary CTA permits diagnostic image quality in patients weighing up to 100 kg. Body weight is a suitable criterion to select patients for low-dose pulmonary CTA.

Analysis of key molecules of the innate immune system in mammary epithelial cells isolated from marker-assisted and conventionally selected cattle

Mastitis is the most prevalent infectious disease in dairy herds. Breeding programs considering mastitis susceptibility were adopted as approaches to improve udder health status. In recent decades, conventional selection criteria based on phenotypic characteristics such as somatic cell score in milk have been widely used to select animals. Recently, approaches to incorporate molecular information have become feasible because of the detection of quantitative trait loci (QTL) affecting mastitis resistance. The aims of the study were to explore molecular mechanisms underlying mastitis resistance and the genetic mechanisms underlying a QTL on Bos taurus chromosome 18 found to influence udder health. Primary cell cultures of mammary epithelial cells from heifers that were selected for high or low susceptibility to mastitis were established. Selection based on estimated pedigree breeding value or on the basis of marker-assisted selection using QTL information was implemented. The mRNA expression of 10 key molecules of the innate immune system was measured using quantitative real-time PCR after 1, 6, and 24 h of challenge with heat-inactivated mastitis pathogens (Escherichia coli and Staphylococcus aureus) and expression levels in the high and low susceptibility groups were compared according to selection criteria. In the marker-assisted selection groups, mRNA expression in cells isolated from less-susceptible animals was significantly elevated for toll-like receptor 2, tumor necrosis factor-alpha, IL-1beta, IL-6, IL-8, RANTES (regulated upon activation, normal t-cell expressed and secreted), complement factor C3, and lactoferrin. In the estimated pedigree breeding value groups, mRNA expression was significantly elevated only for V-rel reticuloendotheliosis viral oncogene homolog A, IL-1 beta, and RANTES. These observations provide first insights into genetically determined divergent reactions to pathogens in the bovine mammary gland and indicate that the application of QTL information could be a successful tool for the selection of animals resistant to mastitis.

Antiplatelets versus Anticoagulants for the Treatment of Cervical Artery Dissection: Bayesian Meta-Analysis

OBJECTIVE To compare the effects of antiplatelets and anticoagulants on stroke and death in patients with acute cervical artery dissection. DESIGN Systematic review with Bayesian meta-analysis. DATA SOURCES The reviewers searched MEDLINE and EMBASE from inception to November 2012, checked reference lists, and contacted authors. STUDY SELECTION Studies were eligible if they were randomised, quasi-randomised or observational comparisons of antiplatelets and anticoagulants in patients with cervical artery dissection. DATA EXTRACTION Data were extracted by one reviewer and checked by another. Bayesian techniques were used to appropriately account for studies with scarce event data and imbalances in the size of comparison groups. DATA SYNTHESIS Thirty-seven studies (1991 patients) were included. We found no randomised trial. The primary analysis revealed a large treatment effect in favour of antiplatelets for preventing the primary composite outcome of ischaemic stroke, intracranial haemorrhage or death within the first 3 months after treatment initiation (relative risk 0.32, 95% credibility interval 0.12 to 0.63), while the degree of between-study heterogeneity was moderate (τ(2) = 0.18). In an analysis restricted to studies of higher methodological quality, the possible advantage of antiplatelets over anticoagulants was less obvious than in the main analysis (relative risk 0.73, 95% credibility interval 0.17 to 2.30). CONCLUSION In view of these results and the safety advantages, easier usage and lower cost of antiplatelets, we conclude that antiplatelets should be given precedence over anticoagulants as a first line treatment in patients with cervical artery dissection unless results of an adequately powered randomised trial suggest the opposite.

Effect of psychological interventions on depressive symptoms in long-term rehabilitation after an acquired brain injury: a systematic review and meta-analysis

OBJECTIVE To summarize empirical studies on the effectiveness of psychological interventions in long-term rehabilitation after an acquired brain injury (ABI) in reducing depressive symptoms. DATA SOURCES A systematic literature search was conducted on MEDLINE, PsycINFO, Embase, and CINAHL to identify articles published between January 1990 and October 2011. Search terms included the 3 concepts (1) "brain injur*" or "stroke," (2) "psychotherap*" or "therapy" or "intervention" or "rehabilitation," and (3) "depress*." STUDY SELECTION Studies evaluating psychological interventions in patients after ABI were included. Time since injury was on average more than 1 year. Trials reported data on validated depression questionnaires before and after the psychological intervention. DATA EXTRACTION Two independent reviewers extracted information from the sample, the intervention, and the outcome of the included studies and calculated effect sizes (ESs) from depression questionnaires. Thirteen studies were included in a pre-post analysis. Seven studies were eligible for a meta-analysis of ESs in active interventions and control conditions. DATA SYNTHESIS Pre-post ESs were significant in 4 of 13 studies. The overall ES of .69 (95% confidence interval [CI], .29-1.09) suggests a medium effectiveness of psychological interventions on depressive symptoms compared with control conditions. Moderator analysis of the number of sessions and adequate randomization procedure did not show significant ES differences between strata. Studies with adequate randomization did not, however, suggest the effectiveness of psychological interventions on depressive symptoms after ABI. CONCLUSIONS Psychological interventions are a promising treatment option for depressive symptoms in long-term rehabilitation after ABI. Since only a few adequately randomized controlled trials (RCTs) exist, more RCTs are required to confirm this initial finding.

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10−12). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the ‘intermediate phenotype’ nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host–pathogen interaction.

Genomic signatures of relaxed disruptive selection associated with speciation reversal in whitefish

Background: Speciation reversal: the erosion of species differentiation via an increase in introgressive hybridization due to the weakening of previously divergent selection regimes, is thought to be an important, yet poorly understood, driver of biodiversity loss. Our study system, the Alpine whitefish (Coregonus spp.) species complex is a classic example of a recent postglacial adaptive radiation: forming an array of endemic lake flocks, with the independent origination of similar ecotypes among flocks. However, many of the lakes of the Alpine radiation have been seriously impacted by anthropogenic nutrient enrichment, resulting in a collapse in neutral genetic and phenotypic differentiation within the most polluted lakes. Here we investigate the effects of eutrophication on the selective forces that have shaped this radiation, using population genomics. We studied eight sympatric species assemblages belonging to five independent parallel adaptive radiations, and one species pair in secondary contact. We used AFLP markers, and applied FST outlier (BAYESCAN, DFDIST) and logistic regression analyses (MATSAM), to identify candidate regions for disruptive selection in the genome and their associations with adaptive traits within each lake flock. The number of outlier and adaptive trait associated loci identified per lake were then regressed against two variables (historical phosphorus concentration and contemporary oxygen concentration) representing the strength of eutrophication. Results: Whilst we identify disruptive selection candidate regions in all lake flocks, we find similar trends, across analysis methods, towards fewer disruptive selection candidate regions and fewer adaptive trait/candidate loci associations in the more polluted lakes. Conclusions: Weakened disruptive selection and a concomitant breakdown in reproductive isolating mechanisms in more polluted lakes has lead to increased gene flow between coexisting Alpine whitefish species. We hypothesize that the resulting higher rates of interspecific recombination reduce either the number or extent of genomic islands of divergence surrounding loci evolving under disruptive natural selection. This produces the negative trend seen in the number of selection candidate loci recovered during genome scans of whitefish species flocks, with increasing levels of anthropogenic eutrophication: as the likelihood decreases that AFLP restriction sites will fall within regions of heightened genomic divergence and therefore be classified as FST outlier loci. This study explores for the first time the potential effects of human-mediated relaxation of disruptive selection on heterogeneous genomic divergence between coexisting species.

Critical Analysis of Bladder Sparing with Trimodal Therapy in Muscle-invasive Bladder Cancer: A Systematic Review.

CONTEXT Aims of bladder preservation in muscle-invasive bladder cancer (MIBC) are to offer a quality-of-life advantage and avoid potential morbidity or mortality of radical cystectomy (RC) without compromising oncologic outcomes. Because of the lack of a completed randomised controlled trial, oncologic equivalence of bladder preservation modality treatments compared with RC remains unknown. OBJECTIVE This systematic review sought to assess the modern bladder-preservation treatment modalities, focusing on trimodal therapy (TMT) in MIBC. EVIDENCE ACQUISITION A systematic literature search in the PubMed and Cochrane databases was performed from 1980 to July 2013. EVIDENCE SYNTHESIS Optimal bladder-preservation treatment includes a safe transurethral resection of the bladder tumour as complete as possible followed by radiation therapy (RT) with concurrent radiosensitising chemotherapy. A standard radiation schedule includes external-beam RT to the bladder and limited pelvic lymph nodes to an initial dose of 40Gy, with a boost to the whole bladder to 54Gy and a further tumour boost to a total dose of 64-65Gy. Radiosensitising chemotherapy with phase 3 trial evidence in support exists for cisplatin and mitomycin C plus 5-fluorouracil. A cystoscopic assessment with systematic rebiopsy should be performed at TMT completion or early after TMT induction. Thus, nonresponders are identified early to promptly offer salvage RC. The 5-yr cancer-specific survival and overall survival rates range from 50% to 82% and from 36% to 74%, respectively, with salvage cystectomy rates of 25-30%. There are no definitive data to support the benefit of using of neoadjuvant or adjuvant chemotherapy. Critical to good outcomes is proper patient selection. The best cancers eligible for bladder preservation are those with low-volume T2 disease without hydronephrosis or extensive carcinoma in situ. CONCLUSIONS A growing body of accumulated data suggests that bladder preservation with TMT leads to acceptable outcomes and therefore may be considered a reasonable treatment option in well-selected patients. PATIENT SUMMARY Treatment based on a combination of resection, chemotherapy, and radiotherapy as bladder-sparing strategies may be considered as a reasonable treatment option in properly selected patients.

Hebbian analysis of the transformation of medial entorhinal grid-cell inputs to hippocampal place fields.

The discovery of grid cells in the medial entorhinal cortex (MEC) permits the characterization of hippocampal computation in much greater detail than previously possible. The present study addresses how an integrate-and-fire unit driven by grid-cell spike trains may transform the multipeaked, spatial firing pattern of grid cells into the single-peaked activity that is typical of hippocampal place cells. Previous studies have shown that in the absence of network interactions, this transformation can succeed only if the place cell receives inputs from grids with overlapping vertices at the location of the place cell's firing field. In our simulations, the selection of these inputs was accomplished by fast Hebbian plasticity alone. The resulting nonlinear process was acutely sensitive to small input variations. Simulations differing only in the exact spike timing of grid cells produced different field locations for the same place cells. Place fields became concentrated in areas that correlated with the initial trajectory of the animal; the introduction of feedback inhibitory cells reduced this bias. These results suggest distinct roles for plasticity of the perforant path synapses and for competition via feedback inhibition in the formation of place fields in a novel environment. Furthermore, they imply that variability in MEC spiking patterns or in the rat's trajectory is sufficient for generating a distinct population code in a novel environment and suggest that recalling this code in a familiar environment involves additional inputs and/or a different mode of operation of the network.

Frequency-Dependent Selection Predicts Patterns of Radiations and Biodiversity

Most empirical studies support a decline in speciation rates through time, although evidence for constant speciation rates also exists. Declining rates have been explained by invoking pre-existing niches, whereas constant rates have been attributed to non-adaptive processes such as sexual selection and mutation. Trends in speciation rate and the processes underlying it remain unclear, representing a critical information gap in understanding patterns of global diversity. Here we show that the temporal trend in the speciation rate can also be explained by frequency-dependent selection. We construct a frequency-dependent and DNA sequence-based model of speciation. We compare our model to empirical diversity patterns observed for cichlid fish and Darwin's finches, two classic systems for which speciation rates and richness data exist. Negative frequency-dependent selection predicts well both the declining speciation rate found in cichlid fish and explains their species richness. For groups like the Darwin's finches, in which speciation rates are constant and diversity is lower, speciation rate is better explained by a model without frequency-dependent selection. Our analysis shows that differences in diversity may be driven by incipient species abundance with frequency-dependent selection. Our results demonstrate that genetic-distance-based speciation and frequency-dependent selection are sufficient to explain the high diversity observed in natural systems and, importantly, predict decay through time in speciation rate in the absence of pre-existing niches.

Detection and sequence analysis of a nickel-induced mutation in a retroviral model system

We have developed a novel way to assess the mutagenicity of environmentally important metal carcinogens, such as nickel, by creating a positive selection system based upon the conditional expression of a retroviral transforming gene. The target gene is the v-mos gene in MuSVts110, a murine retrovirus possessing a growth temperature dependent defect in expression of the transforming gene due to viral RNA splicing. In normal rat kidney cells infected with MuSVts110 (6m2 cells), splicing of the MuSVts110 RNA to form the mRNA from which the transforming protein, p85$\sp{\rm gag-mos}$, is translated is growth-temperature dependent, occurring at 33 C and below but not at 39 C and above. This splicing "defect" is mediated by cis-acting viral sequences. Nickel chloride treatment of 6m2 cells followed by growth at 39 C, allowed the selection of "revertant" cells which constitutively express p85$\sp{\rm gag-mos}$ due to stable changes in the viral RNA splicing phenotype, suggesting that nickel, a carcinogen whose mutagenicity has not been well established, could induce mutations in mammalian genes. We also show by direct sequencing of PCR-amplified integrated MuSVts110 DNA from a 6m2 nickel-revertant cell line that the nickel-induced mutation affecting the splicing phenotype is a cis-acting 70-base duplication of a region of the viral DNA surrounding the 3$\sp\prime$ splice site. These findings provide the first example of the molecular basis for a nickel-induced DNA lesion and establish the mutagenicity of this potent carcinogen. ^