Epigenetic domains found in mouse embryonic stem cells via a hidden Markov model

<p>Abstract</p> <p>Background</p> <p>Epigenetics is an important layer of transcriptional control necessary for cell-type specific gene regulation. Recent studies have shown significant epigenetic patterns associated with developmental stages and diseases. However, previous studies have been mostly limited to focal epigenetic patterns, whereas methods for analyzing large-scale organizations are still lacking.</p> <p>Results</p> <p>We developed a hidden Markov model (HMM) approach for detecting the types and locations of epigenetic domains from multiple histone modifications. We used this method to analyze a published ChIP-seq dataset of five histone modification marks (H3K4me2, H3K4me3, H3K27me3, H3K9me3, and H3K36me3) in mouse embryonic stem (ES) cells. We identified three types of domains, corresponding to active, non-active, and null states. In total, our three-state HMM identified 258 domains in the mouse genome containing 9.6 genes on average. These domains were validated by a number of criteria. The largest domains correspond to olfactory receptor (OR) gene clusters. Each <it>Hox </it>gene cluster also forms a separate epigenetic domain. We found that each type of domain is associated with distinct biological functions and structural changes during early cell differentiation.</p> <p>Conclusions</p> <p>The HMM approach successfully detects domains of consistent epigenetic patterns from ChIP-seq data, providing new insights into the role of epigenetics in long-range gene regulation.</p

Activity Patterns and Pollution Exposure

In recent times there has been increasing interest in modelling policies to limit impacts of air pollution due to motor vehicles. Impacts of air pollution on human health and comfort depend on the relationship between the distribution of pollutants and the spatial distribution of the urban population. As emissions, weather conditions and the location of the population vary with time of day, day of month and season of the year, the problem is complex. Travel demand models with activity-based approaches and a focus on the overall structure of activity/travel relations, not only spatially, but temporally can make a valuable contribution. They are often used to estimate emissions due to the travel patterns of city populations but may equally be used to provide distributions of urban populations during the day. A case study for Melbourne, Australia demonstrates the use of activity data in the estimation of population exposure. Additionally the study shows some marked differences in activity between seasons and even greater the differences in effect of that activity on exposure to air pollution. Numbers of cities will have seasonal pollutant patterns similar to Melbourne and others will benefit from exploring such patterns

A new approach to the chronology of caves 268/272/275 in the Dunhuang Mogao Grottoes: combining radiocarbon dates and archaeological information within a Bayesian statistical framework

The construction chronology of three of the earliest Dunhuang Mogao Grottoes (Caves 268, 272, and 275) has been the subject of ongoing debate for over half a century. This chronology is a crucial topic in terms of further understanding of the establishment of the Dunhuang Mogao Grottoes, early Buddhism in the Gansu corridor, and its relationship with Buddhism developed in the Central Plains. Building upon archaeological, art historical and radiocarbon (14C) dating studies, we integrate new 14C data with these previously published findings utilizing Bayesian statistical modeling to improve the chronological resolution of this issue. Thus, we determine that all three of these caves were constructed around AD 410–440, suggesting coeval rather than sequential construction

The Rational Agent Benchmark for Data Visualization

Understanding how helpful a visualization is from experimental results is difficult because the observed performance is confounded with aspects of the study design, such as how useful the information that is visualized is for the task. We develop a rational agent framework for designing and interpreting visualization experiments. Our framework conceives two experiments with the same setup: one with behavioral agents (human subjects), the other one with a hypothetical rational agent. A visualization is evaluated by comparing the expected performance of behavioral agents to that of rational agent under different assumptions. Using recent visualization decision studies from the literature, we demonstrate how the framework can be used to pre-experimentally evaluate the experiment design by bounding the expected improvement in performance from having access to visualizations, and post-experimentally to deconfound errors of information extraction from errors of optimization, among other analyses

Tissue specific induction of p62/sqstm1 by farnesoid X receptor

Background: Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily and is a ligand-activated transcription factor essential for maintaining liver and intestinal homeostasis. FXR is protective against carcinogenesis and inflammation in liver and intestine as demonstrated by the development of inflammation and tumors in the liver and intestine of FXR knock-out mice. However, mechanisms for the protective effects of FXR are not completely understood. This study reports a novel role of FXR in regulating expression of Sqstm1, which encodes for p62 protein. p62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-κB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm1 may serve as a protective mechanism. Methods and Results: This study showed that FXR bound to the Sqstm1 gene in both mouse livers and ileums as determined by chromatin immunoprecipitation. In addition, FXR activation enhanced transcriptional activation of Sqstm1 in vitro. However, wild-type mice treated with GW4064, a synthetic FXR ligand, showed that FXR activation induced mRNA and protein expression of Sqstm1/p62 in ileum, but not in liver. Interestingly, FXR-transgenic mice showed induced mRNA expression of Sqstm1 in both liver and ileum compared to wild-type mice. Conclusions: Our current study has identified a novel role of FXR in regulating the expression of p62, a key factor in protein degradation and cell signaling. Regulation of p62 by FXR indicates tissue-specific and gene-dosage effects. Furthermore, FXR-mediated induction of p62 may implicate a protective mechanism of FXR. © 2012 Williams et al

A Case of Chronic Eosinophilic Leukemia in a Patient With Recurrent Cough, Dyspnea, and Eosinophilia

We report the case of a 40-year-old man with no significant past medical history who had been hospitalized multiple times over the course of one year with recurring cough, dyspnea, pruritic rash, and variable degrees of eosinophilia. He was variably diagnosed with asthma and pneumonia. After his last hospitalization with severe symptoms, the patient was referred for pulmonary evaluation where hypereosinophilia (HE) led to a hematologic workup. Fluorescence in situ hybridization revealed the FIP1L1-PDGFRA gene fusion and bone marrow analysis confirmed a diagnosis of chronic eosinophilic leukemia. The patient was treated with daily imatinib and prednisone and he was symptom-free at a four-week follow-up examination

EVM: Incorporating Model Checking into Exploratory Visual Analysis

Visual analytics (VA) tools support data exploration by helping analysts quickly and iteratively generate views of data which reveal interesting patterns. However, these tools seldom enable explicit checks of the resulting interpretations of data -- e.g., whether patterns can be accounted for by a model that implies a particular structure in the relationships between variables. We present EVM, a data exploration tool that enables users to express and check provisional interpretations of data in the form of statistical models. EVM integrates support for visualization-based model checks by rendering distributions of model predictions alongside user-generated views of data. In a user study with data scientists practicing in the private and public sector, we evaluate how model checks influence analysts' thinking during data exploration. Our analysis characterizes how participants use model checks to scrutinize expectations about data generating process and surfaces further opportunities to scaffold model exploration in VA tools

Glossitis in an older non-corgi dog: Diagnosis and long-term follow-up.

A 9-year-old spayed female 18.8 kg mixed breed boxer dog was referred for evaluation of a 7-month history of difficulty swallowing and prehending food, regurgitation, hypersalivation, and an abnormal dorsiflexion of the tongue. Prior to referral, a barium study was performed, which revealed a mildly dilated esophagus. Treatment with sucralfate, cisapride, and prednisone was initiated. Physical examination revealed bilateral, symmetric atrophy of the temporalis muscles, dorsiflexion of the distal aspect of the tongue with concurrent muscle atrophy, and a reduced gag reflex. Electrodiagnostic examinations revealed spontaneous electrical activity in the muscles of mastication and tongue. Biopsies from the right temporalis, tongue, and biceps femoris muscles were collected. An immune-mediated myositis with fibrosis, scattered CD3, CD4, and CD8+ T-lymphocytes, and upregulation of markers for major histocompatibility antigens were observed in the tongue and temporalis muscles. The dog was treated with a tapering course of prednisone over 2 months and cyclosporine long-term. The dog was maintained on cyclosporine alone for &gt; 2 years and clinical signs remained static, although multiple episodes of aspiration pneumonia occurred. Ultimately, euthanasia was performed due to chronic kidney disease with associated anemia, lethargy, and anorexia

Switchable resolution in soft x-ray tomography of single cells.

The diversity of living cells, in both size and internal complexity, calls for imaging methods with adaptable spatial resolution. Soft x-ray tomography (SXT) is a three-dimensional imaging technique ideally suited to visualizing and quantifying the internal organization of single cells of varying sizes in a near-native state. The achievable resolution of the soft x-ray microscope is largely determined by the objective lens, but switching between objectives is extremely time-consuming and typically undertaken only during microscope maintenance procedures. Since the resolution of the optic is inversely proportional to the depth of focus, an optic capable of imaging the thickest cells is routinely selected. This unnecessarily limits the achievable resolution in smaller cells and eliminates the ability to obtain high-resolution images of regions of interest in larger cells. Here, we describe developments to overcome this shortfall and allow selection of microscope optics best suited to the specimen characteristics and data requirements. We demonstrate that switchable objective capability advances the flexibility of SXT to enable imaging cells ranging in size from bacteria to yeast and mammalian cells without physically modifying the microscope, and we demonstrate the use of this technology to image the same specimen with both optics

An interactive visualization and data portal tool (PALTIDE) for relative sea level and palaeotidal simulations of the northwest European shelf seas since the Last Glacial Maximum

ABSTRACTRelative sea level (RSL) predictions based on glacial isostatic adjustment (GIA) simulations and palaeotidal predictions generated by hydrodynamic models using GIA‐generated palaeotopographies are available in the published literature, and datasets are available via data repositories. However, these data are often difficult to extract for specific locations or timeslices, requiring users to request datasets from corresponding authors. To overcome the intractability of these data and to enable users to interrogate datasets themselves without requiring offline requests, we have developed PALTIDE, an online visualization tool with intuitive user interface accessible at https://shiny.bangor.ac.uk/paleotidal/. The model domain for this interactive visualization tool is the northwest European continental shelf, covering the period from the Last Glacial Maximum (LGM) to the present day, and is based on previous GIA simulations by Bradley and colleagues and hydrodynamic simulations using Regional Ocean Modelling System (ROMS) published by Ward and colleagues. The tool is developed in R and utilizes a number of packages including shiny and bslib for the frontend, and arrow, raster and the tidyverse for backend data processing. The tool enables visualizations and data downloads for RSL, tidal amplitude and tide‐dependent parameters for any location within the model domain over 1000‐year timesteps from the LGM to the present