219 research outputs found
Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors
Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh
receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine
sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6^(L9’S*)
receptors. α6^(L9’S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and
rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6 α4* pentamers, as α6^(L9’S) mice
lacking α4 subunits displayed essentially normal behavior. In α6^(L9’S) mice, receptor numbers are normal, but loss of α4 subunits leads to
fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits,
implicating α6α4β2* nAChRs in α6^(L9’S) mouse behaviors. In brain slices, we applied electrochemical measurements to study
control of DA release by α6^(L9’S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials
selectively in α6^(L9’S), but not WT or α4KO/ α6^(L9’S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced
extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6^(L9’S) presynaptic terminals, as there was no
difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in
cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the
DA system
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GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity.
Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness
Inferring hidden Markov models from noisy time sequences: a method to alleviate degeneracy in molecular dynamics
We present a new method for inferring hidden Markov models from noisy time
sequences without the necessity of assuming a model architecture, thus allowing
for the detection of degenerate states. This is based on the statistical
prediction techniques developed by Crutchfield et al., and generates so called
causal state models, equivalent to hidden Markov models. This method is
applicable to any continuous data which clusters around discrete values and
exhibits multiple transitions between these values such as tethered particle
motion data or Fluorescence Resonance Energy Transfer (FRET) spectra. The
algorithms developed have been shown to perform well on simulated data,
demonstrating the ability to recover the model used to generate the data under
high noise, sparse data conditions and the ability to infer the existence of
degenerate states. They have also been applied to new experimental FRET data of
Holliday Junction dynamics, extracting the expected two state model and
providing values for the transition rates in good agreement with previous
results and with results obtained using existing maximum likelihood based
methods.Comment: 19 pages, 9 figure
The metabolism of anabolic-androgenic steroids in the greyhound
BACKGROUND Effective control of the use of anabolic-androgenic steroids (AASs) in animal sports is essential in order to ensure both animal welfare and integrity. In order to better police their use in Australian and New Zealand greyhound racing, thorough metabolic studies have been carried out on a range of registered human and veterinary AASs available in the region. RESULTS Canine metabolic data are presented for the AASs boldenone, danazol, ethylestrenol, mesterolone, methandriol, nandrolone and norethandrolone. The principal Phase I metabolic processes observed were the reduction of A-ring unsaturations and/or 3-ketones with either 3α,5β- or 3β,5α-stereochemistry, the oxidation of secondary 17β-hydroxyl groups and 16α-hydroxylation. The Phase II β-glucuronylation of sterol metabolites was extensive. CONCLUSION The presented data have enabled the effective analysis of AASs and their metabolites in competition greyhound urine samples.Australian Research Council LP077483
ALMA reveals a stable rotating gas disk in a paradoxical low-mass, ultra-dusty galaxy at z = 4.274
We report ALMA detections of [CII] and dust continuum in Az9, a
multiply-imaged galaxy behind the Frontier Field cluster MACSJ0717.5+3745. The
bright [CII] emission line provides a spectroscopic redshift of z = 4.274. This
strongly lensed (mu = 7 +/- 1) galaxy has an intrinsic stellar mass of only 2e9
Msun and a total star formation rate of 26 Msun/yr (~80% of which is dust
obscured). Using public magnification maps, we reconstruct the [CII] emission
in the source plane to reveal a stable, rotation-dominated disk with V/sigma =
5.3, which is > 2x higher than predicted from simulations for similarly
high-redshift, low-mass galaxies. In the source plane, the [CII] disk has a
half-light radius of 1.8 kpc and, along with the dust, is spatially offset from
the peak of the stellar light by 1.4 kpc. Az9 is not deficient in [CII];
L[CII]/LIR = 0.0027 consistent with local and high redshift normal star forming
galaxies. While dust-obscured star formation is expected to dominate in higher
mass galaxies, such a large reservoir of dust and gas in a lower mass disk
galaxy 1.4 Gyr after the Big Bang challenges our picture of early galaxy
evolution. Furthermore, the prevalence of such low-mass dusty galaxies has
important implications for the selection of the highest redshift dropout
galaxies with JWST. As one of the lowest stellar mass galaxies at z > 4 to be
detected in dust continuum and [CII], Az9 is an excellent laboratory in which
to study early dust enrichment in the interstellar medium.Comment: Accepted for publication in ApJ Letter
Impairment of Coronary Arteriolar Endothelium-Dependent Dilation after Multi-Walled Carbon Nanotube Inhalation: A Time-Course Study
Engineered nanomaterials have been developed for widespread applications due to many highly unique and desirable characteristics. The purpose of this study was to assess pulmonary inflammation and subepicardial arteriolar reactivity in response to multi-walled carbon nanotube (MWCNT) inhalation and evaluate the time course of vascular alterations. Rats were exposed to MWCNT aerosols producing pulmonary deposition. Pulmonary inflammation via bronchoalveolar lavage and MWCNT translocation from the lungs to systemic organs was evident 24 h post-inhalation. Coronary arterioles were evaluated 24–168 h post-exposure to determine microvascular response to changes in transmural pressure, endothelium-dependent and -independent reactivity. Myogenic responsiveness, vascular smooth muscle reactivity to nitric oxide, and α-adrenergic responses all remained intact. However, a severe impact on endothelium-dependent dilation was observed within 24 h after MWCNT inhalation, a condition which improved, but did not fully return to control after 168 h. In conclusion, results indicate that MWCNT inhalation not only leads to pulmonary inflammation and cytotoxicity at low lung burdens, but also a low level of particle translocation to systemic organs. MWCNT inhalation also leads to impairments of endothelium-dependent dilation in the coronary microcirculation within 24 h, a condition which does not fully dissipate within 168 h. The innovations within the field of nanotechnology, while exciting and novel, can only reach their full potential if toxicity is first properly assessed
Why People Dual Screen Political Debates and Why It Matters for Democratic Engagement
Dual screening during televised election debates is a new domain in which political elites and journalists seek to influence audience attitudes and behavior. But to what extent do non-elite dual screeners seek to influence others, particularly their social media followers, social media users in general, and even politicians and journalists? And how does this behavior affect short- and longer-term engagement with election campaigns? Using unique, event-based, panel survey data from the main 2015 UK general election debate (Wave 1 = 2,351; Wave 2 = 1,168) we reveal the conditions under which people experience agency, empowerment, and engagement now that social media have reconfigured broadcast political television
Comb-Based Radio-Frequency Photonic Filters with Rapid Tunability and High Selectivity
Photonic technologies have received considerable attention for enhancement of
radio-frequency (RF) electrical systems, including high-frequency analog signal
transmission, control of phased arrays, analog-to-digital conversion, and
signal processing. Although the potential of radio-frequency photonics for
implementation of tunable electrical filters over broad RF bandwidths has been
much discussed, realization of programmable filters with highly selective
filter lineshapes and rapid reconfigurability has faced significant challenges.
A new approach for RF photonic filters based on frequency combs offers a
potential route to simultaneous high stopband attenuation, fast tunability, and
bandwidth reconfiguration. In one configuration tuning of the RF passband
frequency is demonstrated with unprecedented (~40 ns) speed by controlling the
optical delay between combs. In a second, fixed filter configuration, cascaded
four-wave mixing simultaneously broadens and smoothes comb spectra, resulting
in Gaussian RF filter lineshapes exhibiting extremely high (>60 dB) main lobe
to sidelobe suppression ratio and (>70 dB) stopband attenuation.Comment: Updated the submission with the most recent version of the pape
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