907 research outputs found
Failure Time of Loaded Wooden Beams During Fire
A model is presented for predicting the failure time of loaded wooden beams of rectangular cross-section exposed to elevated temperatures or to fire. Failure times calculated by the model were compared to failure times measured in this study using 19.05 mm x 19.05 mm simply supported southern pine beams, and to failure times measured by the National Bureau of Standards during the fire of a full scale room. Reasonable agreements were found between the calculated failure times and the data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69007/2/10.1177_073490418300100407.pd
Interaction between androgen receptor and coregulator SLIRP is regulated by Ack1 tyrosine kinase and androgen
Aberrant activation of the androgen receptor (AR) may play a critical role in castration resistant prostate cancer. After ligand binding, AR is recruited to the androgen responsive element (ARE) sequences on the DNA where AR interaction with coactivators and corepressors modulates transcription. We demonstrated that phosphorylation of AR at Tyr-267 by Ack1/TNK2 tyrosine kinase results in nuclear translocation, DNA binding, and androgen-dependent gene transcription in a low androgen environment. In order to dissect downstream mechanisms, we searched for proteins whose interaction with AR was regulated by Ack1. SLIRP (SRA stem-loop interacting RNA binding protein) was identified as a candidate protein. Interaction between AR and SLIRP was disrupted by Ack1 kinase activity as well as androgen or heregulin treatment. The noncoding RNA, SRA, was required for AR-SLIRP interaction. SLIRP was bound to ARE’s of AR target genes in the absence of androgen. Treatment with androgen or heregulin led to dissociation of SLIRP from the ARE. Whole transcriptome analysis of SLIRP knockdown in androgen responsive LNCaP cells showed that SLIRP affects a significant subset of androgen-regulated genes. Our data suggest that Ack1 kinase and androgen regulate interaction between AR and SLIRP and that SLIRP functions as a coregulator of AR with properties of a corepressor in a context-dependent manner
ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer
Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies. By cistrome profiling of endogenous androgen receptor (AR) versus an AR splice variant, AR-V7, Cai et al. uncovered non-canonical pathways uniquely targeted by AR-V7 and ZFX, a previously unknown AR-V7 partner. Targeting cofactors (ZFX or BRD4) or non-canonical downstream pathways of AR-V7 provides potential therapeutic ways for treating prostate cancer
The Flare-energy Distributions Generated by Kink-unstable Ensembles of Zero-net-current Coronal Loops
It has been proposed that the million degree temperature of the corona is due
to the combined effect of barely-detectable energy releases, so called
nanoflares, that occur throughout the solar atmosphere. Alas, the nanoflare
density and brightness implied by this hypothesis means that conclusive
verification is beyond present observational abilities. Nevertheless, we
investigate the plausibility of the nanoflare hypothesis by constructing a
magnetohydrodynamic (MHD) model that can derive the energy of a nanoflare from
the nature of an ideal kink instability. The set of energy-releasing
instabilities is captured by an instability threshold for linear kink modes.
Each point on the threshold is associated with a unique energy release and so
we can predict a distribution of nanoflare energies. When the linear
instability threshold is crossed, the instability enters a nonlinear phase as
it is driven by current sheet reconnection. As the ensuing flare erupts and
declines, the field transitions to a lower energy state, which is modelled by
relaxation theory, i.e., helicity is conserved and the ratio of current to
field becomes invariant within the loop. We apply the model so that all the
loops within an ensemble achieve instability followed by energy-releasing
relaxation. The result is a nanoflare energy distribution. Furthermore, we
produce different distributions by varying the loop aspect ratio, the nature of
the path to instability taken by each loop and also the level of radial
expansion that may accompany loop relaxation. The heating rate obtained is just
sufficient for coronal heating. In addition, we also show that kink instability
cannot be associated with a critical magnetic twist value for every point along
the instability threshold
Enhancing Next-Generation Sequencing-Guided Cancer Care Through Cognitive Computing
Background: Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human “molecular tumor boards” (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB. Materials and Methods: One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis. Results: Using a WfG-curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker-selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case. Conclusion: These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up-to-date availability of clinical trials. Implications for Practice: The results of this study demonstrate that the interpretation and actionability of somatic next-generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost-effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data
What is the Nature of EUV Waves? First STEREO 3D Observations and Comparison with Theoretical Models
One of the major discoveries of the Extreme ultraviolet Imaging Telescope
(EIT) on SOHO were intensity enhancements propagating over a large fraction of
the solar surface. The physical origin(s) of the so-called `EIT' waves is still
strongly debated. They are considered to be either wave (primarily fast-mode
MHD waves) or non-wave (pseudo-wave) interpretations. The difficulty in
understanding the nature of EUV waves lies with the limitations of the EIT
observations which have been used almost exclusively for their study. Their
limitations are largely overcome by the SECCHI/EUVI observations on-board the
STEREO mission. The EUVI telescopes provide high cadence, simultaneous
multi-temperature coverage, and two well-separated viewpoints. We present here
the first detailed analysis of an EUV wave observed by the EUVI disk imagers on
December 07, 2007 when the STEREO spacecraft separation was .
Both a small flare and a CME were associated with the wave cadence, and single
temperature and viewpoint coverage. These limitations are largely overcome by
the SECCHI/EUVI observations on-board the STEREO mission. The EUVI telescopes
provide high cadence, simultaneous multi-temperature coverage, and two
well-separated viewpoints. Our findings give significant support for a
fast-mode interpretation of EUV waves and indicate that they are probably
triggered by the rapid expansion of the loops associated with the CME.Comment: Solar Physics, 2009, Special STEREO Issue, in pres
Solar Intranetwork Magnetic Elements: bipolar flux appearance
The current study aims to quantify characteristic features of bipolar flux
appearance of solar intranetwork (IN) magnetic elements. To attack such a
problem, we use the Narrow-band Filter Imager (NFI) magnetograms from the Solar
Optical Telescope (SOT) on board \emph{Hinode}; these data are from quiet and
an enhanced network areas. Cluster emergence of mixed polarities and IN
ephemeral regions (ERs) are the most conspicuous forms of bipolar flux
appearance within the network. Each of the clusters is characterized by a few
well-developed ERs that are partially or fully co-aligned in magnetic axis
orientation. On average, the sampled IN ERs have total maximum unsigned flux of
several 10^{17} Mx, separation of 3-4 arcsec, and a lifetime of 10-15 minutes.
The smallest IN ERs have a maximum unsigned flux of several 10^{16} Mx,
separations less than 1 arcsec, and lifetimes as short as 5 minutes. Most IN
ERs exhibit a rotation of their magnetic axis of more than 10 degrees during
flux emergence. Peculiar flux appearance, e.g., bipole shrinkage followed by
growth or the reverse, is not unusual. A few examples show repeated
shrinkage-growth or growth-shrinkage, like magnetic floats in the dynamic
photosphere. The observed bipolar behavior seems to carry rich information on
magneto-convection in the sub-photospheric layer.Comment: 26 pages, 14 figure
Modeling the Subsurface Structure of Sunspots
While sunspots are easily observed at the solar surface, determining their
subsurface structure is not trivial. There are two main hypotheses for the
subsurface structure of sunspots: the monolithic model and the cluster model.
Local helioseismology is the only means by which we can investigate
subphotospheric structure. However, as current linear inversion techniques do
not yet allow helioseismology to probe the internal structure with sufficient
confidence to distinguish between the monolith and cluster models, the
development of physically realistic sunspot models are a priority for
helioseismologists. This is because they are not only important indicators of
the variety of physical effects that may influence helioseismic inferences in
active regions, but they also enable detailed assessments of the validity of
helioseismic interpretations through numerical forward modeling. In this paper,
we provide a critical review of the existing sunspot models and an overview of
numerical methods employed to model wave propagation through model sunspots. We
then carry out an helioseismic analysis of the sunspot in Active Region 9787
and address the serious inconsistencies uncovered by
\citeauthor{gizonetal2009}~(\citeyear{gizonetal2009,gizonetal2009a}). We find
that this sunspot is most probably associated with a shallow, positive
wave-speed perturbation (unlike the traditional two-layer model) and that
travel-time measurements are consistent with a horizontal outflow in the
surrounding moat.Comment: 73 pages, 19 figures, accepted by Solar Physic
The prognostic significance of low-frequency somatic mutations in metastatic cutaneous melanoma
Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) 75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM
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