1,021 research outputs found
Calibration of Computational Models with Categorical Parameters and Correlated Outputs via Bayesian Smoothing Spline ANOVA
It has become commonplace to use complex computer models to predict outcomes
in regions where data does not exist. Typically these models need to be
calibrated and validated using some experimental data, which often consists of
multiple correlated outcomes. In addition, some of the model parameters may be
categorical in nature, such as a pointer variable to alternate models (or
submodels) for some of the physics of the system. Here we present a general
approach for calibration in such situations where an emulator of the
computationally demanding models and a discrepancy term from the model to
reality are represented within a Bayesian Smoothing Spline (BSS) ANOVA
framework. The BSS-ANOVA framework has several advantages over the traditional
Gaussian Process, including ease of handling categorical inputs and correlated
outputs, and improved computational efficiency. Finally this framework is then
applied to the problem that motivated its design; a calibration of a
computational fluid dynamics model of a bubbling fluidized which is used as an
absorber in a CO2 capture system
KAP1 Recruitment of the 7SK snRNP Complex to Promoters Enables Transcription Elongation by RNA Polymerase II
SummaryThe transition from transcription initiation to elongation at promoters of primary response genes (PRGs) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoter-proximal regions in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP) complex. However, it remains unclear how and why the 7SK snRNP is assembled at these sites. Here we report that the transcriptional regulator KAP1 continuously tethers the 7SK snRNP to PRG promoters to facilitate P-TEFb recruitment and productive elongation in response to stimulation. Remarkably, besides PRGs, genome-wide studies revealed that KAP1 and 7SK snRNP co-occupy most promoter-proximal regions containing paused Pol II. Collectively, we provide evidence of an unprecedented mechanism controlling 7SK snRNP delivery to promoter-proximal regions to facilitate "on-site" P-TEFb activation and Pol II elongation
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Creating New β-Globin-Expressing Lentiviral Vectors by High-Resolution Mapping of Locus Control Region Enhancer Sequences.
Hematopoietic stem cell gene therapy is a promising approach for treating disorders of the hematopoietic system. Identifying combinations of cis-regulatory elements that do not impede packaging or transduction efficiency when included in lentiviral vectors has proven challenging. In this study, we deploy LV-MPRA (lentiviral vector-based, massively parallel reporter assay), an approach that simultaneously analyzes thousands of synthetic DNA fragments in parallel to identify sequence-intrinsic and lineage-specific enhancer function at near-base-pair resolution. We demonstrate the power of LV-MPRA in elucidating the boundaries of previously unknown intrinsic enhancer sequences of the human β-globin locus control region. Our approach facilitated the rapid assembly of novel therapeutic βAS3-globin lentiviral vectors harboring strong lineage-specific recombinant control elements capable of correcting a mouse model of sickle cell disease. LV-MPRA can be used to map any genomic locus for enhancer activity and facilitates the rapid development of therapeutic vectors for treating disorders of the hematopoietic system or other specific tissues and cell types
Engineering Proteinase Inihibitor Genes For Plant Defense Against Predators
Small proteinaceous inhibitors (Mr\u3c20,000) of the digestive serine proteinases of animals and microorganisms are found as moderately abundant proteins in storage organs and leaves of many plant genera. The proteins are powerful inhibitors of the digestive enzymes of plant predators and therefore are considered to be part of the array of defensive chemicals of plants. Proteinase inhibitor genes show excellent promise, using DNA technology, to manipulate plant genomes to express these biologically active proteins in order to improve natural defense systems. Members of two unrelated families of serine proteinase inhibitors found in tomato and potato plants, called Inhibitor I (monomer Mr 8000) and Inhibitor II (monomer Mr 12,300), are under both environmental and developmental regulation in different tissues of the plants. Genes coding for wound-inducible Inhibitors I and II have been isolated from both tomato and potato genomes and characterized. Tobacco plants have been transformed with the chimeric genes containing wound-inducible promoters fused with the reporter gene, chloramphenicol acetyl transferase, to assess promoter function and signal transmission. Transacting factors that regulate their expression in response to wounding are also being identified and purified. Intact genes are being employed to transform agriculturally important crop plants to determine their potential usefulness to enhance defensive capabilities of plants against herbivores and pathogens
Type IIb Supernova SN 2011dh: Spectra and Photometry from the Ultraviolet to the Near-Infrared
We report spectroscopic and photometric observations of the Type IIb SN
2011dh obtained between 4 and 34 days after the estimated date of explosion
(May 31.5 UT). The data cover a wide wavelength range from 2,000 Angstroms in
the UV to 2.4 microns in the NIR. Optical spectra provide line profiles and
velocity measurements of HI, HeI, CaII and FeII that trace the composition and
kinematics of the SN. NIR spectra show that helium is present in the atmosphere
as early as 11 days after the explosion. A UV spectrum obtained with the STIS
reveals that the UV flux for SN 2011dh is low compared to other SN IIb. The HI
and HeI velocities in SN 2011dh are separated by about 4,000 km/s at all
phases. We estimate that the H-shell of SN 2011dh is about 8 times less massive
than the shell of SN 1993J and about 3 times more massive than the shell of SN
2008ax. Light curves (LC) for twelve passbands are presented. The maximum
bolometric luminosity of erg s occurred
about 22 days after the explosion. NIR emission provides more than 30% of the
total bolometric flux at the beginning of our observations and increases to
nearly 50% of the total by day 34. The UV produces 16% of the total flux on day
4, 5% on day 9 and 1% on day 34. We compare the bolometric light curves of SN
2011dh, SN 2008ax and SN 1993J. The LC are very different for the first twelve
days after the explosions but all three SN IIb display similar peak
luminosities, times of peak, decline rates and colors after maximum. This
suggests that the progenitors of these SN IIb may have had similar compositions
and masses but they exploded inside hydrogen shells that that have a wide range
of masses. The detailed observations presented here will help evaluate
theoretical models for this supernova and lead to a better understanding of SN
IIb.Comment: 23 pages, 14 figures, 9 tables, accepted by Ap
Hubble Space Telescope and Ground-Based Observations of the Type Iax Supernovae SN 2005hk and SN 2008A
We present Hubble Space Telescope (HST) and ground-based optical and
near-infrared observations of SN 2005hk and SN 2008A, typical members of the
Type Iax class of supernovae (SNe). Here we focus on late-time observations,
where these objects deviate most dramatically from all other SN types. Instead
of the dominant nebular emission lines that are observed in other SNe at late
phases, spectra of SNe 2005hk and 2008A show lines of Fe II, Ca II, and Fe I
more than a year past maximum light, along with narrow [Fe II] and [Ca II]
emission. We use spectral features to constrain the temperature and density of
the ejecta, and find high densities at late times, with n_e >~ 10^9 cm^-3. Such
high densities should yield enhanced cooling of the ejecta, making these
objects good candidates to observe the expected "infrared catastrophe," a
generic feature of SN Ia models. However, our HST photometry of SN 2008A does
not match the predictions of an infrared catastrophe. Moreover, our HST
observations rule out a "complete deflagration" that fully disrupts the white
dwarf for these peculiar SNe, showing no evidence for unburned material at late
times. Deflagration explosion models that leave behind a bound remnant can
match some of the observed properties of SNe Iax, but no published model is
consistent with all of our observations of SNe 2005hk and 2008A.Comment: 20 pages, 15 figure
Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi‐institutional study
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134120/1/ajh24376.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134120/2/ajh24376_am.pd
The electronic medication complete communication (EMC2) study: Rationale and methods for a randomized controlled trial of a strategy to promote medication safety in ambulatory care
AbstractBackgroundAdverse drug events (ADEs) affect millions of patients annually and place a significant burden on the healthcare system. The Food and Drug Administration (FDA) has developed patient safety information for high-risk medications that pose serious public health concerns. However, there are currently few assurances that patients receive this information or are able to identify or respond correctly to ADEs.ObjectiveTo evaluate the effectiveness of the Electronic Medication Complete Communication (EMC2) Strategy to promote safe medication use and reporting of ADEs in comparison to usual care.MethodsThe automated EMC2 Strategy consists of: 1) provider alerts to counsel patients on medication risks, 2) the delivery of patient-friendly medication information via the electronic health record, and 3) an automated telephone assessment to identify potential medication concerns or ADEs. The study will take place in two community health centers in Chicago, IL. Adult, English or Spanish-speaking patients (N=1200) who have been prescribed a high-risk medication will be enrolled and randomized to the intervention arm or usual care based upon practice location. The primary outcomes of the study are medication knowledge, proper medication use, and reporting of ADEs; these will be measured at baseline, 4weeks, and three months. Intervention fidelity as well as barriers and costs of implementation will be evaluated.ConclusionsThe EMC2 Strategy automates a patient-friendly risk communication and surveillance process to promote safe medication use while minimizing clinic burden. This trial seeks to evaluate the effectiveness and feasibility of this strategy in comparison to usual care
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