Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (>200 nt) from the intergenic regions of annotated protein-coding genes. One of the most highly induced lincRNAs in ...macrophages upon TLR ligation is lincRNA-Cox2, which was recently shown to mediate the activation and repression of distinct classes of immune genes in innate immune cells. We report that lincRNA-Cox2, located at chromosome 1 proximal to the PG-endoperoxide synthase 2 (Ptgs2/Cox2) gene, is an early-primary inflammatory gene controlled by NF-κB signaling in murine macrophages. Functionally, lincRNA-Cox2 is required for the transcription of NF-κB-regulated late-primary inflammatory response genes stimulated by bacterial LPS. Specifically, lincRNA-Cox2 is assembled into the switch/sucrose nonfermentable (SWI/SNF) complex in cells after LPS stimulation. This resulting lincRNA-Cox2/SWI/SNF complex can modulate the assembly of NF-κB subunits to the SWI/SNF complex, and ultimately, SWI/SNF-associated chromatin remodeling and transactivation of the late-primary inflammatory-response genes in macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role for NF-κB-induced lincRNA-Cox2 as a coactivator of NF-κB for the transcription of late-primary response genes in innate immune cells through modulation of epigenetic chromatin remodeling.
MicroRNAs (miRNAs), small non-coding regulatory RNAs that regulate gene expression at the post-transcriptional level, are master regulators of a wide array of cellular processes. Altered miRNA ...expression could be a determinant of disease development and/or progression and manipulation of miRNA expression represents a potential avenue of therapy. Exosomes are cell-derived extracellular vesicles that promote cell-cell communication and immunoregulatory functions. These "bioactive vesicles" shuttle various molecules, including miRNAs, to recipient cells. Inappropriate release of miRNAs from exosomes may cause significant alterations in biological pathways that affect disease development, supporting the concept that miRNA-containing exosomes could serve as targeted therapies for particular diseases. This review briefly summarizes recent advances in the biology, function, and therapeutic potential of exosomal miRNAs.
Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy allows studying the structure, dynamics, and interactions of proteins
via
distance ...measurements in the nanometer range. We here give an overview of available spin labels, the strategies for their introduction into proteins, and the associated potentials for protein structural studies
in vitro
and in the context of living cells.
We here review strategies for site-directed spin labeling (SDSL) of proteins and discuss their potential for EPR distance measurements to study protein function
in vitro
and in cells.
We demonstrated how the subcycle evolution of the electric field of light can be used to control the motion of bound electrons. Results are presented for the dissociative ionization of deuterium ...molecules (D₂ rightwards double arrow D⁺ + D), where asymmetric ejection of the ionic fragment reveals that light-driven intramolecular electronic motion before dissociation localizes the electron on one of the two D⁺ ions in a controlled way. The results extend subfemtosecond electron control to molecules and provide evidence of its usefulness in controlling reaction dynamics.
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5.
Direct Measurement of Light Waves Goulielmakis, E.; Uiberacker, M.; Kienberger, R. ...
Science (American Association for the Advancement of Science),
08/2004, Volume:
305, Issue:
5688
Journal Article
Peer reviewed
Open access
The electromagnetic field of visible light performs$\sim 10^{15}$oscillations per second. Although many instruments are sensitive to the amplitude and frequency (or wavelength) of these oscillations, ...they cannot access the light field itself. We directly observed how the field built up and disappeared in a short, few-cycle pulse of visible laser light by probing the variation of the field strength with a 250-attosecond electron burst. Our apparatus allows complete characterization of few-cycle waves of visible, ultraviolet, and/or infrared light, thereby providing the possibility for controlled and reproducible synthesis of ultrabroadband light waveforms.
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Cryptosporidium parvum is a protozoan parasite that infects the gastrointestinal epithelium and causes diarrheal disease worldwide. Innate epithelial immune responses are key mediators of the host's ...defense to C. parvum. MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level and are involved in regulation of both innate and adaptive immune responses. Using an in vitro model of human cryptosporidiosis, we analyzed C. parvum-induced miRNA expression in biliary epithelial cells (i.e., cholangiocytes). Our results demonstrated differential alterations in the mature miRNA expression profile in cholangiocytes following C. parvum infection or lipopolysaccharide stimulation. Database analysis of C. parvum-upregulated miRNAs revealed potential NF-kappaB binding sites in the promoter elements of a subset of miRNA genes. We demonstrated that mir-125b-1, mir-21, mir-30b, and mir-23b-27b-24-1 cluster genes were transactivated through promoter binding of the NF-kappaB p65 subunit following C. parvum infection. In contrast, C. parvum transactivated mir-30c and mir-16 genes in cholangiocytes in a p65-independent manner. Importantly, functional inhibition of selected p65-dependent miRNAs in cholangiocytes increased C. parvum burden. Thus, we have identified a panel of miRNAs regulated through promoter binding of the NF-kappaB p65 subunit in human cholangiocytes in response to C. parvum infection, a process that may be relevant to the regulation of epithelial anti-microbial defense in general.
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In this paper we report on a velocity map imaging spectrometer with the implementation of an on-axis geometry where the electrons travel parallel to the ionizing beam towards the detector. Owing to a ...usually low photon flux from table-top soft x-ray sources, the instrument is optimized for high detector efficiency and high target density. The collinear design offers the possibility to freely choose the state and orientation of the polarization of light fields in streaking experiments. First results of an experiment using THz pulses for streaking using a Xe gas target are presented and compared to the simulated performance of the spectrometer.
Cryptosporidium infects gastrointestinal epithelium and is a leading cause of infectious diarrhea and diarrheal-related death in children worldwide. There are no vaccines and no fully effective ...therapy available for the infection. Type II and III interferon (IFN) responses are important determinants of susceptibility to infection but the role for type I IFN response remains obscure. Cryptosporidium parvum virus 1 (CSpV1) is a double-stranded RNA (dsRNA) virus harbored by Cryptosporidium spp. Here we show that intestinal epithelial conditional Ifnar1
mice (deficient in type I IFN receptor) are resistant to C. parvum infection. CSpV1-dsRNAs are delivered into host cells and trigger type I IFN response in infected cells. Whereas C. parvum infection attenuates epithelial response to IFN-γ, loss of type I IFN signaling or inhibition of CSpV1-dsRNA delivery can restore IFN-γ-mediated protective response. Our findings demonstrate that type I IFN signaling in intestinal epithelial cells is detrimental to intestinal anti-C. parvum defense and Cryptosporidium uses CSpV1 to activate type I IFN signaling to evade epithelial antiparasitic response.
NADPH oxidases (NOX), catalyzing the reduction of molecular oxygen to form the superoxide radical anion (•O₂⁻) and hydrogen peroxide (H₂O₂), are involved in several pathological conditions, such as ...stroke, diabetes, atherosclerosis, but also in chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis. GKT136901 is a novel NOX-1/4 inhibitor with potential application in the areas of diabetic nephropathy, stroke, or neurodegeneration. In the present study, we investigated additional pharmacological activities of the compound with respect to direct free radical scavenging. GKT136901 did not interact with nitric oxide (•NO), •O₂⁻, or hydroxyl radicals (•OH), but it acted as selective scavenger of peroxynitrite (PON) already in the submicromolar concentration range. Alpha synuclein (ASYN) is a protein involved in the pathogenesis of Parkinson's disease and a known target for PON-dependent tyrosine nitration. Submicromolar concentrations of GKT136901 prevented tyrosine nitration and di-tyrosine-dependent dimer formation of ASYN by PON as indicated by Western blot and mass spectrometric analysis. GKT136901 itself was degraded when exposed to PON. In a human neuronal cell model, GKT136901 prevented both the depletion of reduced intracellular glutathione, and the degeneration of neurites when present during PON treatment of the cells. When GKT136901 was applied after PON treatment, no protective effect was observed, thus excluding an impact of GKT136901 on cellular death/survival pathways. In summary, selective scavenging of PON is an additional pharmacological property of the NOX-1/4 inhibitor GKT136901, and this may add to the efficiency of the drug in several disease models.
Comprehensive knowledge of the dynamic behaviour of electrons in condensed-matter systems is pertinent to the development of many modern technologies, such as semiconductor and molecular electronics, ...optoelectronics, information processing and photovoltaics. Yet it remains challenging to probe electronic processes, many of which take place in the attosecond (1 as = 10-18 s) regime. In contrast, atomic motion occurs on the femtosecond (1 fs = 10-15 s) timescale and has been mapped in solids in real time using femtosecond X-ray sources. Here we extend the attosecond techniques previously used to study isolated atoms in the gas phase to observe electron motion in condensed-matter systems and on surfaces in real time. We demonstrate our ability to obtain direct time-domain access to charge dynamics with attosecond resolution by probing photoelectron emission from single-crystal tungsten. Our data reveal a delay of approximately 100 attoseconds between the emission of photoelectrons that originate from localized core states of the metal, and those that are freed from delocalized conduction-band states. These results illustrate that attosecond metrology constitutes a powerful tool for exploring not only gas-phase systems, but also fundamental electronic processes occurring on the attosecond timescale in condensed-matter systems and on surfaces.
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