Tolerance to cannabinoid agonists can develop through desensitization of the cannabinoid receptor 1 (CB1) following prolonged administration. Desensitization results from phosphorylation of CB1 by a ...G protein-coupled receptor kinase (GRK), and subsequent association of the receptor with arrestin. Mice expressing a mutant form of CB1, in which the serine residues at two putative phosphorylation sites necessary for desensitization have been replaced by non-phosphorylatable alanines (S426A/S430A), display reduced tolerance to Δ9-tetrahydrocannabinol (Δ9-THC). Tolerance to the antinociceptive effects of WIN55,212-2 was delayed in S426A/S430A mutants using the tail-flick and formalin tests. However, tolerance to the antinociceptive effects of once daily CP55,940 injections was not significantly delayed in S426A/S430A mutant mice using either of these tests. Interestingly, the dose response curve shifts for the hypothermic and antinociceptive effects of CP55,940 that were induced by chronic treatment with this agonist in wild-type mice were blocked in S426A/S430A mutant mice. Assessment of mechanical allodynia in mice exhibiting chronic cisplatin-evoked neuropathic pain found that tolerance to the anti-allodynic effects WIN55,212-2 but not CP55,940 was delayed in S426A/S430A mice compared to wild-type littermates. Despite these deficits in tolerance, S426A/S430A mutant mice eventually developed tolerance to both WIN55,212-2 and CP55,940 for all pain assays that were examined, suggesting that other mechanisms likely contribute to tolerance for these cannabinoid agonists. These findings suggest that GRK- and βarrestin2-mediated desensitization of CB1 may strongly contribute to the rate of tolerance to the antinociceptive effects of WIN55,212-2, and raises the possibility of agonist-specific mechanisms of cannabinoid tolerance.
•S426A/S430A mutation delays tolerance to WIN55,212-2.•GRK/β-arrestin-mediated CB1 desensitization facilitates tolerance to WIN55,212.•Tolerance to the hypothermic effects of CP55,940 is delayed in S426A/S430A mice.•S426A/S430A increased sensitivity to the antinociceptive effects of CP55,940.
The incidence of new onset visual disturbances in emergency departments across the country is frequent. A detailed history of events and thoughtful physical examination may produce a diagnosis; ...however, atypical cases may require further diagnostic testing to explain symptoms. We present a case of presumed increased intracranial pressure with atypical findings on diagnostic testing, which allowed our team to explore a broader differential diagnosis. This clinical reasoning article will benefit students, residents, and attendings alike to continue to uncover etiologies for symptoms of increased intracranial pressure and review differential diagnoses in similar presentations.
Abstract
Using photometry collected with the Zwicky Transient Facility, we are conducting an ongoing survey for binary systems with short orbital periods (
with the goal of identifying new ...gravitational-wave sources detectable by the upcoming Laser Interferometer Space Antenna (LISA). We present a sample of 15 binary systems discovered thus far, with orbital periods ranging from 6.91 to 56.35 minutes. Of the 15 systems, seven are eclipsing systems that do not show signs of significant mass transfer. Additionally, we have discovered two AM Canum Venaticorum systems and six systems exhibiting primarily ellipsoidal variations in their lightcurves. We present follow-up spectroscopy and high-speed photometry confirming the nature of these systems, estimates of their LISA signal-to-noise ratios, and a discussion of their physical characteristics.
The detonation of a helium shell on a white dwarf (WD) has been proposed as a possible explosion triggering mechanism for SNe Ia. Here, we report ZTF 18aaqeasu (SN 2018byg/ATLAS 18pqq), a peculiar ...Type I supernova, consistent with being a helium-shell double-detonation. With a rise time of 18 days from explosion, the transient reached a peak absolute magnitude of MR −18.2 mag, exhibiting a light curve akin to sub-luminous SN 1991bg-like SNe Ia, albeit with an unusually steep increase in brightness within a week from explosion. Spectra taken near peak light exhibit prominent Si absorption features together with an unusually red color (g − r 2 mag) arising from nearly complete line blanketing of flux blueward of 5000 . This behavior is unlike any previously observed thermonuclear transient. Nebular phase spectra taken at and after 30 days from peak light reveal evidence of a thermonuclear detonation event dominated by Fe-group nucleosynthesis. We show that the peculiar properties of ZTF 18aaqeasu are consistent with the detonation of a massive ( 0.15 ) helium shell on a sub-Chandrasekhar mass ( 0.75 ) WD after including mixing of 0.2 of material in the outer ejecta. These observations provide evidence of a likely rare class of thermonuclear supernovae arising from detonations of massive helium shells.
We describe and report first results from PALM-3000, the second-generation astronomical adaptive optics (AO) facility for the 5.1 m Hale telescope at Palomar Observatory. PALM-3000 has been ...engineered for high-contrast imaging and emission spectroscopy of brown dwarfs and large planetary mass bodies at near-infrared wavelengths around bright stars, but also supports general natural guide star use to V approx = 17. Using its unique 66 x 66 actuator deformable mirror, PALM-3000 has thus far demonstrated residual wave front errors of 141 nm rms under ~1" seeing conditions. PALM-3000 can provide phase conjugation correction over a 6".4 x 6".4 working region at lambda = 2.2 mu m, or full electric field (amplitude and phase) correction over approximately one-half of this field. With optimized back-end instrumentation, PALM-3000 is designed to enable 10 super(-7) contrast at 1" angular separation, including post-observation speckle suppression processing. While continued optimization of the AO system is ongoing, we have already successfully commissioned five back-end instruments and begun a major exoplanet characterization survey, Project 1640.
Study search and selection is central to conducting Evidence Based Software Engineering (EBSE) research, including Systematic Literature Reviews and Systematic Mapping Studies. Thus, selecting ...relevant studies and excluding irrelevant studies, is critical. Prior research argues that study selection is subject to researcher bias, and the time required to review and select relevant articles is a target for optimization.
This research proposes two training-by-example classifiers that are computationally simple, do not require extensive training or tuning, ensure inclusion/exclusion consistency, and reduce researcher study selection time: one based on Vector Space Models (VSM), and a second based on Latent Semantic Analysis (LSA).
Algorithm evaluation is accomplished through Monte-Carlo Cross-Validation simulations, in which study subsets are randomly chosen from the corpus for training, with the remainder classified by the algorithm. The classification results are then assessed for recall (a measure of completeness), precision (a measure of exactness) and researcher efficiency savings (reduced proportion of corpus studies requiring manual review as a result of algorithm use). A second smaller simulation is conducted for external validation.
VSM algorithms perform better in recall; LSA algorithms perform better in precision. Recall improves with larger training sets with a higher proportion of truly relevant studies. Precision improves with training sets with a higher portion of irrelevant studies, without a significant impact from the training set size. The algorithms reduce the influence of researcher bias and are found to significantly improve researcher efficiency.
To improve recall, the findings recommend VSM and a large training set including as many truly relevant studies as possible. If precision and efficiency are most critical, the findings suggest LSA and a training set including a large proportion of truly irrelevant studies.
The Palomar Transient Factory (PTF) is a multiepochal robotic survey of the northern sky that acquires data for the scientific study of transient and variable astrophysical phenomena. The camera and ...telescope provide for wide-field imaging in optical bands. In the five years of operation since first light on 2008 December 13, images taken with Mould-R and SDSS-g′ camera filters have been routinely acquired on a nightly basis (weather permitting), and two different Hα filters were installed in 2011 May (656 and 663 nm). The PTF image-processing and data-archival program at the Infrared Processing and Analysis Center (IPAC) is tailored to receive and reduce the data, and, from it, generate and preserve astrometrically and photometrically calibrated images, extracted source catalogs, and co-added reference images. Relational databases have been deployed to track these products in operations and the data archive. The fully automated system has benefited by lessons learned from past IPAC projects and comprises advantageous features that are potentially incorporable into other ground-based observatories. Both off-the-shelf and in-house software have been utilized for economy and rapid development. The PTF data archive is curated by the NASA/IPAC Infrared Science Archive (IRSA). A state-of-the-art custom Web interface has been deployed for downloading the raw images, processed images, and source catalogs from IRSA. Access to PTF data products is currently limited to an initial public data release (M81, M44, M42, SDSS Stripe 82, and the Kepler Survey Field). It is the intent of the PTF collaboration to release the full PTF data archive when sufficient funding becomes available.
Traffic analysis procedures are becoming more robust over time. However, there is still significant room for improvement both in practitioners’ adoption of robust methods and in robustness of the ...methods themselves. One example of oversimplified practice involves peak hour or 30th highest hour analysis, which fails to capture the impacts of varying demands and operating conditions. To address this limitation, detailed reliability modelling procedures were developed for the Highway Capacity Manual (HCM), but these procedures bring challenging input data and calibration requirements. A new generation of data‐driven tools is capable of real‐time congestion identification, but their performance measures are only beginning to improve and evolve. Finally, comparing and ranking congested locations (i.e. bottlenecks) on the basis of experience and judgment lacks credibility unless backed by quantitative results. This study discusses the development of new and innovative performance measures for congestion measurement. A case study of ranking eight real‐world bottlenecks based on the proposed measures and existing HCM measures produced new insights that could improve both approaches. Ideally, these new insights and methods would be accepted by agencies and/or commercial products for a new level of robustness in congestion measurement.
The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in ...the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits. This study assessed the anti-nociceptive effects of a selective cannabinoid 2 receptor agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with morphine. JWH-133 produces dose-dependent anti-nociception during both the acute and inflammatory phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. After eleven once-daily injections of 1 mg/JWH-133, no tolerance was observed in the formalin test. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant cannabinoid 2 receptor and mu-opioid receptor interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle-treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine, suggesting opioid and cannabinoid 2 receptor cross-tolerance is unidirectional. However, preliminary data suggest co-administration of JWH-133 with morphine modestly attenuates morphine tolerance. Isobolographic analysis revealed that co-administration of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that cannabinoid 2 receptor may functionally interact with mu-opioid receptor to modulate anti-nociception in the formalin test.
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