In February 2007, Zemeckis and Walt Disney Studios chairman Dick Cook announced plans for a new performance capture film company devoted to CG-created, 3-D movies.[30] The company, ImageMovers Digital, created films using the performance capture technology, with Zemeckis directing most of the projects which Disney distributed and marketed worldwide. Zemeckis used the performance capture technology again in his film, Beowulf, to retell the Anglo-Saxon epic poem of the same name. It featured Ray Winstone, Angelina Jolie, and Anthony Hopkins. Neil Gaiman, who co-wrote the adaptation with Roger Avary, described the film as a "cheerfully violent and strange take on the Beowulf legend."[31] The film was released on November 16, 2007, to mostly positive reviews and grossed $196 million worldwide.
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Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.
We present new 40Ar/ 39Ar ages and paleomagnetic data for São Miguel island, Azores. Paleomagnetic samples were obtained for 34 flows and one dike; successful mean paleomagnetic directions were obtained for 28 of these 35 sites. 40Ar/ 39Ar age determinations on 12 flows from the Nordeste complex were attempted successfully: ages obtained are between 0.78 Ma and 0.88 Ma, in contrast to published K-Ar ages of 1 Ma to 4 Ma. Our radiometric ages are consistent with the reverse polarity paleomagnetic field directions, and indicate that the entire exposed part of the Nordeste complex is of a late Matuyama age. The duration of volcanism across São Miguel is significantly less than previously believed, which has important implications for regional melt generation processes, and temporal sampling of the geomagnetic field. Observed stable isotope and trace element trends across the island can be explained, at least in part, by communication between different magma source regions at depth. The 40Ar/ 39Ar ages indicate that our normal polarity paleomagnetic data sample at least 0.1 Myr (0-0.1 Ma) and up to 0.78 Myr (0-0.78 Ma) of paleosecular variation and our reverse polarity data sample approximately 0.1 Myr (0.78-0.88 Ma) of paleosecular variation. Our results demonstrate that precise radiometric dating of numerous flows sampled is essential to accurate inferences of long-term geomagnetic field behavior. Negative inclination anomalies are observed for both the normal and reverse polarity time-averaged field. Within the data uncertainties, normal and reverse polarity field directions are antipodal, but the reverse polarity field shows a significant deviation from a geocentric axial dipole direction.
The full-length cDNA for the cod (Gadus morhua) StAR was cloned by RT-PCR and library screening using ovarian RNA. From the library screening, 2 size classes of cDNA were obtained; a 1577 bp cDNA (cStAR1) and a 2851 bp cDNA (cStAR2). The cStAR1 cDNA presumably encodes a protein of 286 amino acids. The cStAR2 cDNA was composed of 6 separated sequences that contained all of the coding regions of cStAR1 when added together, but also contained 5 noncoding regions not observed in cStAR1. Polymerase chain reactions of cod genomic DNA produced products slightly larger than cStAR2. The sequence of these products were the same as cStAR2 but revealed one additional noncoding region (intron). Thus, the fish StAR gene contains the same number of exons (7) and introns (6) as observed in mammals, but is approximately half the size of the mammalian gene. Using Northern analysis and RT-PCR, cStAR1 expression was observed only in testes, ovaries and head kidneys. Polymerase chain reaction products were also observed using cDNA from steroidogenic tissues and primers designed to regions specific for cStAR2, indicating that cStAR2 is expressed in tissues and may account for the presence of larger transcripts observed on Northern blots.
The androgen receptor variant AR-V7 is gaining attention as a potential predictive marker for as well as one of the resistance mechanisms to the most current anti-androgen receptor (AR) therapies in castration-resistant prostate cancer (CRPC). Accordingly, development of next-generation drugs that directly or indirectly target AR-V7 signaling is urgently needed. Areas covered: We review proposed mechanisms of drug resistance in relation to AR-V7 status, the mechanisms of generation of AR-V7, and its transcriptome, cistrome, and interactome. Pharmacological agents that interfere with these processes are being developed to counteract pan AR and AR-V7-specific signaling. Also, we address the current status of the preclinical and clinical studies targeting AR-V7 signaling. Expert opinion: AR-V7 is considered a true therapeutic target, however, it remains to be determined if AR-V7 is a principal driver or merely a bystander requiring heterodimerization with co-expressed full-length AR or other variants to drive CRPC progression. While untangling AR-V7 biology, multiple strategies are being developed to counteract drug resistance, including selective blockade of AR-V7 signaling as well as inhibition of pan-AR signaling. Ideally anti-AR therapies will be combined with agents preventing activation and enrichment of AR negative tumor cells that are otherwise depressed by AR activity axis.
Dr. Thomas Marsh (University of Warwick) and colleagues have requested AAVSO coverage of the intriguing binary AR Sco in support of upcoming Newton-XMM observations scheduled for 2016 September 10 15:41 - September 11 02:26 UT. This fascinating binary system is the subject of an exciting paper in the July 2016 issue of Nature (Marsh et al., 2016Natur.537..374M; pre-print version at arXiv ( ). Marsh writes of their research on AR Sco: "...it was down to [the amateurs [who are co-authors] on the paper that we got onto it in the first place. Coverage immediately before, after and (especially) during [the XMM observations] would be great. The most challenging aspect is the time resolution: ideally one wants a cadence
Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs. Here, we report an approach that adds AR-V7 or KRAS status to CTC enumeration, compatible with multiple CTC-isolation platforms. We studied 3 independent CTC-isolation devices (CellCollector, Parsortix, CellSearch) for the evaluation of AR-V7 or KRAS status of CTCs with in situ padlock probe technology. Padlock probes allow highly specific detection and visualization of transcripts on a cellular level. We applied padlock probes for detecting AR-V7, androgen receptor full length (AR-FL), and prostate-specific antigen (PSA) in CRPC and KRAS wild-type (wt) and mutant (mut) transcripts in PaCa in CTCs from 46 patients. In situ analysis showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [1-76 rolling circle products (RCPs)/CTC]. In PaCa patients, 40% (6 of 15) had KRAS mut expressing CTCs with 1 to 8 RCPs/CTC. In situ padlock probe analysis revealed CTCs with no detectable cytokeratin expression but positivity for AR-V7 or KRAS mut transcripts. Padlock probe technology enables quantification of AR-V7, AR-FL, PSA, and KRAS mut/wt transcripts in CTCs. The technology is easily applicable in routine laboratories and compatible with multiple CTC-isolation devices. 2017 American Association for Clinical Chemistry. 2ff7e9595c
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