306 research outputs found
Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer
In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERΞ²) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with β 55% of them in extragenic DNA regions and an intriguing involvement of the 5β² domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa
Description of Goussia kuehae n. sp. (Apicomplexa: Eimeriidae) infecting the Asian seabass, Lates calcarifer (Bloch)(Perciformes: Latidae), cultured in Malaysian fish farms
Culturing fishes in marine cages is a rapidly
developing area of marine aquaculture. The Asian
seabass Lates calcarifer (Bloch) is a fast growing good
quality fish that is readily cultured in intensive systems
in the South Asian region and in Malaysia in
particular. Although several papers have been published
to date on viral, bacterial, parasitic and fungal
organisms causing diseases in the Asian seabass, the
occurrence of a coccidian infection in this species has
only recently been recorded. We collected sporulated
and unsporulated oo¨cysts of a new species of Goussia
LabbeΒ΄, 1986, from the mucus covering the epithelium
of the intestine of L. calcarifer. This paper provides a
description of Goussia kuehae n. sp. Sporulated
ooΒ¨cysts of this species are ellipsoidal, 37β40 lm in
length and 28β30 lm in width. The ellipsoidal sporocysts
are relatively small, 15.2β17 9 5.7β8 lm, and
located loosely in the oo¨cyst. There are residual bodies
both in the oo¨cysts and the sporocysts. Goussia kuehae
n. sp. differs from all known species of Goussia in the large size of the oo¨cysts and in having two types of
oo¨cyst residuum
Synthesis and Investigation of a Radioiodinated F3 Peptide Analog as a SPECT Tumor Imaging Radioligand
A radioiodinated derivative of the tumor-homing F3 peptide, (N-(2-{3-[125I]Iodobenzoyl}aminoethyl)maleimide-F3Cys peptide, [125I]IBMF3 was developed for investigation as a SPECT tumor imaging radioligand. For this purpose, we custom synthesized a modified F3 peptide analog (F3Cys) incorporating a C-terminal cysteine residue for site-specific attachment of a radioiodinated maleimide conjugating group. Initial proof-of-concept Fluorescence studies conducted with AlexaFluor 532 C5 maleimide-labeled F3Cys showed distinct membrane and nuclear localization of F3Cys in MDA-MB-435 cells. Additionally, F3Cys conjugated with NIR fluorochrome AlexaFluor 647 C2 maleimide demonstrated high tumor specific uptake in melanoma cancer MDA-MB-435 and lung cancer A549 xenografts in nude mice whereas a similarly labeled control peptide did not show any tumor uptake. These results were also confirmed by ex vivo tissue analysis. No-carrier-added [125I]IBMF3 was synthesized by a radioiododestannylation approach in 73% overall radiochemical yield. In vitro cell uptake studies conducted with [125I]IBMF3 displayed a 5-fold increase in its cell uptake at 4 h when compared to controls. SPECT imaging studies with [125I]IBMF3 in tumor bearing nude mice showed clear visualization of MDA-MB-435 xenografts on systemic administration. These studies demonstrate a potential utility of F3 peptide-based radioligands for tumor imaging with PET or SPECT techniques
RNA Polymerase II Pausing Downstream of Core Histone Genes Is Different from Genes Producing Polyadenylated Transcripts
Recent genome-wide chromatin immunoprecipitation coupled high throughput sequencing (ChIP-seq) analyses performed in various eukaryotic organisms, analysed RNA Polymerase II (Pol II) pausing around the transcription start sites of genes. In this study we have further investigated genome-wide binding of Pol II downstream of the 3β² end of the annotated genes (EAGs) by ChIP-seq in human cells. At almost all expressed genes we observed Pol II occupancy downstream of the EAGs suggesting that Pol II pausing 3β² from the transcription units is a rather common phenomenon. Downstream of EAGs Pol II transcripts can also be detected by global run-on and sequencing, suggesting the presence of functionally active Pol II. Based on Pol II occupancy downstream of EAGs we could distinguish distinct clusters of Pol II pause patterns. On core histone genes, coding for non-polyadenylated transcripts, Pol II occupancy is quickly dropping after the EAG. In contrast, on genes, whose transcripts undergo polyA tail addition [poly(A)+], Pol II occupancy downstream of the EAGs can be detected up to 4β6 kb. Inhibition of polyadenylation significantly increased Pol II occupancy downstream of EAGs at poly(A)+ genes, but not at the EAGs of core histone genes. The differential genome-wide Pol II occupancy profiles 3β² of the EAGs have also been confirmed in mouse embryonic stem (mES) cells, indicating that Pol II pauses genome-wide downstream of the EAGs in mammalian cells. Moreover, in mES cells the sharp drop of Pol II signal at the EAG of core histone genes seems to be independent of the phosphorylation status of the C-terminal domain of the large subunit of Pol II. Thus, our study uncovers a potential link between different mRNA 3β² end processing mechanisms and consequent Pol II transcription termination processes
Temporal feedback control of high-intensity laser pulses to optimize ultrafast heating of atomic clusters
We describe how active feedback routines can be applied at a limited repetition rate (5 Hz) to optimize high-power (> 10 TW) laser interactions with clustered gases. Optimization of x-ray production from an argon cluster jet, using a genetic algorithm, approximately doubled the measured energy through temporal modification of the 150 mJ driving laser pulse. This approach achieved an increased radiation yield through exploration of a multi-dimensional parameter space, without requiring detailed a priori knowledge of the complex cluster dynamics. The optimized laser pulses exhibited a slow rising edge to the intensity profile, which enhanced the laser energy coupling into the cluster medium, compared to the optimally compressed FWHM pulse (40 fs). Our work suggests that this technique can be more widely utilized for control of intense pulsed secondary radiation from petawatt-class laser systems
Non-nociceptive roles of opioids in the CNS: opioids' effects on neurogenesis, learning, memory and affect.
Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours
Laser wakefield acceleration with active feedback at 5 Hz
We describe the use of a genetic algorithm to apply active feedback to a laser wakefield accelerator at a higher power (10 TW) and a lower repetition rate (5 Hz) than previous work. The temporal shape of the drive laser pulse was adjusted automatically to optimize the properties of the electron beam. By changing the software configuration, different properties could be improved. This included the total accelerated charge per bunch, which was doubled, and the average electron energy, which was increased from 22 to 27 MeV. Using experimental measurements directly to provide feedback allows the system to work even when the underlying acceleration mechanisms are not fully understood, and, in fact, studying the optimized pulse shape might reveal new insights into the physical processes responsible. Our work suggests that this technique, which has already been applied with low-power lasers, can be extended to work with petawatt-class laser systems
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