85 research outputs found
Astrocyte Sensitivity to Dopamine in Culture and \u3cem\u3eEx Vivo\u3c/em\u3e
Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. This thesis illustrates effects of dopamine on cultured astrocytes and astrocytes in brain slices (ex vivo). In striatal cultures, extracellular dopamine triggered changes in astrocytic Ca2+ signaling and rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation, but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. To isolate possible mechanisms underlying these structural and functional changes, whole-genome RNA sequencing was used in identifying prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) motif, suggesting involvement of chromatin restructuring in the nucleus. Specifically, results show that cultured astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring and concerted expression of gene networks. To examine astrocyte response to behaviorally relevant dopamine signals, astrocyte morphological and molecular profiles in ventral striatum (nucleus accumbens core; NAcC) and dorsolateral striatum were characterized following cocaine self-administration training on an extended access schedule. Findings illustrate that extended cocaine experience resulted in decreased numbers of GFAP+ cells and primary process number in the ventral striatum. This was associated with an increase in connexin 30 mRNA, an astrocyte-astrocyte interaction gene. In the dorsolateral striatum, there was an observed increase in length of GFAP+ primary processes and downregulation of SPARC (astrocyte-neuron interaction gene) mRNA
Morphogenic Effects Of Dopamine In Cultured Rat Hippocampal Astrocytes
Dopamine is critical for processing of reward and addictive behaviors brought about by drugs of abuse. Scientific investigation of drugs of abuse and their effects on CNS function has traditionally been directed at understanding the role of neurons. However, astrocytes, which constitute approximately half of all human brain cells, play a dynamic role in many essential nervous system functions, including neurotransmission, ion homeostasis, and immune defense. Dopamine effects on astrocytes have been historically understudied, yet research indicates that astrocytes express dopamine receptors and are sensitive to dopaminergic activity. Importantly, astrocytes, comprise a morphologically heterogeneous population of cells, and a distinction between polygonal protoplasmic and stellated fibrous astrocytes in various CNS regions has long been acknowledged. However, the molecular and functional implications of this heterogeneity are largely unknown. Using an in vitro model of elevated extracellular dopamine exposure, our evidence reveals a fast and dramatic dopamine-induced switch from a protoplasmic to a fibrous-like morphology in cultures of rat hippocampal astrocytes. A one hour exposure to dopamine (75ÎĽM) produced an average of 4.5 more processes per astrocyte accompanied by a significant decrease in GFAP-positive area. Treatment with dopamine receptor antagonists prior to dopamine exposure significantly blunted dopamine effects on astrocyte morphology. Importantly, brief one hour treatment with dopamine was found to upregulate mRNA for ST8SiaI (a marker of fibrous/type 2 astrocytes), and downregulate mRNA for Ran2 (a marker of protoplasmic cells/type 1 astrocytes). Quantitative RT-PCR analysis revealed a dopamine-induced upregulation of DRD1, DRD2, and DRD3 mRNA. Together these findings support the hypothesis that excess extracellular dopamine, through action on an astrocyte-bound dopamine receptor, induces alterations in astrocytic morphology and molecular profile. Functional implications of such changes in drug abuse, a condition associated with elevated dopamine signaling, remain to be examine
Reductively Responsive siRNA-Conjugated Hydrogel Nanoparticles for Gene Silencing
A critical need still remains for effective delivery of RNA interference (RNAi) therapeutics to target tissues and cells. Self-assembled lipid- and polymer-based systems have been most extensively explored for transfection with small interfering RNA (siRNA) in liver and cancer therapies. Safety and compatibility of materials implemented in delivery systems must be ensured to maximize therapeutic indices. Hydrogel nanoparticles of defined dimensions and compositions, prepared via a particle molding process that is a unique off-shoot of soft lithography known as PRINT (Particle Replication in Non-wetting Templates), were explored in these studies as delivery vectors. Initially, siRNA was encapsulated in particles through electrostatic association and physical entrapment. Dose-dependent gene silencing was elicited by PEGylated hydrogels at low siRNA doses without cytotoxicity. To prevent disassociation of cargo from particles after systemic administration or during post-fabrication processing for surface functionalization, a polymerizable siRNA pro-drug conjugate with a degradable, disulfide linkage was prepared. Triggered release of siRNA from the prodrug hydrogels was observed under a reducing environment while cargo retention and integrity were maintained under physiological conditions. Gene silencing efficiency and cytocompatibility were optimized by screening the amine content of the particles. When appropriate control siRNA cargos were loaded into hydrogels, gene knockdown was only encountered for hydrogels containing releasable, target-specific siRNAs, accompanied by minimal cell death. Further investigation into shape, size, and surface decoration of siRNA-conjugated hydrogels should enable efficacious targeted in vivo RNAi therapies
Causal structures and causal boundaries
We give an up-to-date perspective with a general overview of the theory of
causal properties, the derived causal structures, their classification and
applications, and the definition and construction of causal boundaries and of
causal symmetries, mostly for Lorentzian manifolds but also in more abstract
settings.Comment: Final version. To appear in Classical and Quantum Gravit
The Temporal Development of Fatty Infiltrates in the Neck Muscles Following Whiplash Injury: An Association with Pain and Posttraumatic Stress
Radiological findings associated with poor recovery following whiplash injury remain elusive. Muscle fatty infiltrates (MFI) in the cervical extensors on magnetic resonance imaging (MRI) in patients with chronic pain have been observed. Their association with specific aspects of pain and psychological factors have yet to be explored longitudinally.44 subjects with whiplash injury were enrolled at 4 weeks post-injury and classified at 6 months using scores on the Neck Disability Index as recovered, mild and moderate/severe. A measure for MFI and patient self-report of pain, loss of cervical range of movement and posttraumatic stress disorder (PTSD) were collected at 4 weeks, 3 months and 6 months post-injury. The effects of time and group and the interaction of time by group on MFI were determined. We assessed the mediating effect of posttraumatic stress and cervical range of movement on the longitudinal relationship between initial pain intensity and MFI. There was no difference in MFI across all groups at enrollment. MFI values increased in the moderate/severe group and were significantly higher in comparison to the recovered and mild groups at 3 and 6 months. No differences in MFI values were found between the mild and recovered groups. Initial severity of PTSD symptoms mediated the relationship between pain intensity and MFI at 6 months. Initial ROM loss did not.MFI in the cervical extensors occur soon following whiplash injury and suggest the possibility for the occurrence of a more severe injury with subsequent PTSD in patients with persistent symptoms
Stream denitrification across biomes and its response to anthropogenic nitrate loading
Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 452 (2008): 202-205, doi:10.1038/nature06686.Worldwide, anthropogenic addition of bioavailable nitrogen (N) to the
biosphere is increasing and terrestrial ecosystems are becoming increasingly N
saturated, causing more bioavailable N to enter groundwater and surface waters.
Large-scale N budgets show that an average of about 20-25% of the N added to the
biosphere is exported from rivers to the ocean or inland basins, indicating
substantial sinks for N must exist in the landscape. Streams and rivers may be
important sinks for bioavailable N owing to their hydrologic connections with
terrestrial systems, high rates of biological activity, and streambed sediment
environments that favor microbial denitrification. Here, using data from 15N
tracer experiments replicated across 72 streams and 8 regions representing several
biomes, we show that total biotic uptake and denitrification of nitrate increase with
stream nitrate concentration, but that the efficiency of biotic uptake and
denitrification declines as concentration increases, reducing the proportion of instream
nitrate that is removed from transport. Total uptake of nitrate was related
to ecosystem photosynthesis and denitrification was related to ecosystem
respiration. Additionally, we use a stream network model to demonstrate that
excess nitrate in streams elicits a disproportionate increase in the fraction of nitrate
that is exported to receiving waters and reduces the relative role of small versus
large streams as nitrate sinks.Funding for this research was provided by the National Science
Foundation
The ABC130 barrel module prototyping programme for the ATLAS strip tracker
For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector,
consisting of silicon pixel, silicon strip and transition radiation
sub-detectors, will be replaced with an all new 100 % silicon tracker, composed
of a pixel tracker at inner radii and a strip tracker at outer radii. The
future ATLAS strip tracker will include 11,000 silicon sensor modules in the
central region (barrel) and 7,000 modules in the forward region (end-caps),
which are foreseen to be constructed over a period of 3.5 years. The
construction of each module consists of a series of assembly and quality
control steps, which were engineered to be identical for all production sites.
In order to develop the tooling and procedures for assembly and testing of
these modules, two series of major prototyping programs were conducted: an
early program using readout chips designed using a 250 nm fabrication process
(ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm
processing (ABC130 and HCC130 chips). This second generation of readout chips
was used for an extensive prototyping program that produced around 100
barrel-type modules and contributed significantly to the development of the
final module layout. This paper gives an overview of the components used in
ABC130 barrel modules, their assembly procedure and findings resulting from
their tests.Comment: 82 pages, 66 figure
Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.
BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment
Mise en évidence d’un contrôle volontaire des naissances dans des populations pré-transitionnelles: Le cas de 6 villages allemands, 1766–1863
Follow up of GW170817 and its electromagnetic counterpart by Australian-led observing programmes
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor
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