149 research outputs found
The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of âTail Wags Dogâ Experiments
This work is licensed under a Creative Commons Attribution 4.0 International License.(â)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPÎłS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). âBodyâ and âtailâ interactions with opioid receptors (a subset of Portogheseâs message-address theory) were used for molecular modeling and simulations, where the âaddressâ can be considered the âbodyâ of the hydromorphone molecule and the âmessageâ delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/Îź potency ratio of 1.2 in the ([35S]GTPÎłS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.NIDA grant P30 DA13429NIDA grant DA039997NIDA grant DA018151NIDA grant DA035857NIDA grant DA047574NIH Intramural Research Programs of the National Institute on Drug AbuseNational Institute of Alcohol Abuse and AlcoholismNIH Intramural Research Programs of the National Institute on Drug AbuseNIH Intramural Research Program through the Center for Information TechnologyNIH Intramural Research Programs of the National Institute on Drug Abus
The Atacama Cosmology Telescope: Two-Season ACTPol Spectra and Parameters
We present the temperature and polarization angular power spectra measured by
the Atacama Cosmology Telescope Polarimeter (ACTPol). We analyze night-time
data collected during 2013-14 using two detector arrays at 149 GHz, from 548
deg of sky on the celestial equator. We use these spectra, and the spectra
measured with the MBAC camera on ACT from 2008-10, in combination with Planck
and WMAP data to estimate cosmological parameters from the temperature,
polarization, and temperature-polarization cross-correlations. We find the new
ACTPol data to be consistent with the LCDM model. The ACTPol
temperature-polarization cross-spectrum now provides stronger constraints on
multiple parameters than the ACTPol temperature spectrum, including the baryon
density, the acoustic peak angular scale, and the derived Hubble constant.
Adding the new data to planck temperature data tightens the limits on damping
tail parameters, for example reducing the joint uncertainty on the number of
neutrino species and the primordial helium fraction by 20%.Comment: 23 pages, 25 figure
Polytopic membrane protein folding at L17 in the ribosome tunnel initiates cyclical changes at the translocon
Interaction between L17 in the ribosome tunnel and folded nascent chain transmembrane segments during multi-spanning membrane protein synthesis triggers structural rearrangements in the ribosome that cause switching between cytosolic and ER lumenal targeting of the growing polypeptide
International Experience of Mechanical Thrombectomy During the COVID-19 Pandemic: Insights from STAR and ENRG
Background: In response to the COVID-19 pandemic, many centers altered stroke triage protocols for the protection of their providers. However, the effect of workflow changes on stroke patients receiving mechanical thrombectomy (MT) has not been systematically studied.
Methods: A prospective international study was launched at the initiation of the COVID-19 pandemic. All included centers participated in the Stroke Thrombectomy and Aneurysm Registry (STAR) and Endovascular Neurosurgery Research Group (ENRG). Data was collected during the peak months of the COVID-19 surge at each site. Collected data included patient and disease characteristics. A generalized linear model with logit link function was used to estimate the effect of general anesthesia (GA) on in-hospital mortality and discharge outcome controlling for confounders.
Results: 458 patients and 28 centers were included from North America, South America, and Europe. Five centers were in high-COVID burden counties (HCC) in which 9/104 (8.7%) of patients were positive for COVID-19 compared with 4/354 (1.1%) in low-COVID burden counties (LCC) (P<0.001). 241 patients underwent pre-procedure GA. Compared with patients treated awake, GA patients had longer door to reperfusion time (138 vs 100 min, P=<0.001). On multivariate analysis, GA was associated with higher probability of in-hospital mortality (RR 1.871, P=0.029) and lower probability of functional independence at discharge (RR 0.53, P=0.015).
Conclusion: We observed a low rate of COVID-19 infection among stroke patients undergoing MT in LCC. Overall, more than half of the patients underwent intubation prior to MT, leading to prolonged door to reperfusion time, higher in-hospital mortality, and lower likelihood of functional independence at discharge.info:eu-repo/semantics/publishedVersio
Evaluating the impact of MEDLINE filters on evidence retrieval: study protocol
<p>Abstract</p> <p>Background</p> <p>Rather than searching the entire MEDLINE database, clinicians can perform searches on a filtered set of articles where relevant information is more likely to be found. Members of our team previously developed two types of MEDLINE filters. The 'methods' filters help identify clinical research of high methodological merit. The 'content' filters help identify articles in the discipline of renal medicine. We will now test the utility of these filters for physician MEDLINE searching.</p> <p>Hypothesis</p> <p>When a physician searches MEDLINE, we hypothesize the use of filters will increase the number of relevant articles retrieved (increase 'recall,' also called sensitivity) and decrease the number of non-relevant articles retrieved (increase 'precision,' also called positive predictive value), compared to the performance of a physician's search unaided by filters.</p> <p>Methods</p> <p>We will survey a random sample of 100 nephrologists in Canada to obtain the MEDLINE search that they would first perform themselves for a focused clinical question. Each question we provide to a nephrologist will be based on the topic of a recently published, well-conducted systematic review. We will examine the performance of a physician's unaided MEDLINE search. We will then apply a total of eight filter combinations to the search (filters used in isolation or in combination). We will calculate the recall and precision of each search. The filter combinations that most improve on unaided physician searches will be identified and characterized.</p> <p>Discussion</p> <p>If these filters improve search performance, physicians will be able to search MEDLINE for renal evidence more effectively, in less time, and with less frustration. Additionally, our methodology can be used as a proof of concept for the evaluation of search filters in other disciplines.</p
Chemical Genetics Reveals Bacterial and Host Cell Functions Critical for Type IV Effector Translocation by Legionella pneumophila
Delivery of effector proteins is a process widely used by bacterial pathogens to subvert host cell functions and cause disease. Effector delivery is achieved by elaborate injection devices and can often be triggered by environmental stimuli. However, effector export by the L. pneumophila Icm/Dot Type IVB secretion system cannot be detected until the bacterium encounters a target host cell. We used chemical genetics, a perturbation strategy that utilizes small molecule inhibitors, to determine the mechanisms critical for L. pneumophila Icm/Dot activity. From a collection of more than 2,500 annotated molecules we identified specific inhibitors of effector translocation. We found that L. pneumophila effector translocation in macrophages requires host cell factors known to be involved in phagocytosis such as phosphoinositide 3-kinases, actin and tubulin. Moreover, we found that L. pneumophila phagocytosis and effector translocation also specifically require the receptor protein tyrosine phosphate phosphatases CD45 and CD148. We further show that phagocytosis is required to trigger effector delivery unless intimate contact between the bacteria and the host is artificially generated. In addition, real-time analysis of effector translocation suggests that effector export is rate-limited by phagocytosis. We propose a model in which L. pneumophila utilizes phagocytosis to initiate an intimate contact event required for the translocation of pre-synthesized effector molecules. We discuss the need for host cell participation in the initial step of the infection and its implications in the L. pneumophila lifestyle. Chemical genetic screening provides a novel approach to probe the host cell functions and factors involved in hostâpathogen interactions
The Atacama Cosmology Telescope: High-resolution component-separated maps across one-third of the sky
Observations of the millimeter sky contain valuable information on a number
of signals, including the blackbody cosmic microwave background (CMB), Galactic
emissions, and the Compton- distortion due to the thermal Sunyaev-Zel'dovich
(tSZ) effect. Extracting new insight into cosmological and astrophysical
questions often requires combining multi-wavelength observations to spectrally
isolate one component. In this work, we present a new arcminute-resolution
Compton- map, which traces out the line-of-sight-integrated electron
pressure, as well as maps of the CMB in intensity and E-mode polarization,
across a third of the sky (around 13,000 sq.~deg.). We produce these through a
joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release
4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from
the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We
present detailed verification of an internal linear combination pipeline
implemented in a needlet frame that allows us to efficiently suppress Galactic
contamination and account for spatial variations in the ACT instrument noise.
These maps provide a significant advance, in noise levels and resolution, over
the existing \textit{Planck} component-separated maps and will enable a host of
science goals including studies of cluster and galaxy astrophysics, inferences
of the cosmic velocity field, primordial non-Gaussianity searches, and
gravitational lensing reconstruction of the CMB.Comment: The Compton-y map and associated products will be made publicly
available upon publication of the paper. The CMB T and E mode maps will be
made available when the DR6 maps are made publi
The Atacama Cosmology Telescope: DR6 Gravitational Lensing Map and Cosmological Parameters
We present cosmological constraints from a gravitational lensing mass map
covering 9400 sq. deg. reconstructed from CMB measurements made by the Atacama
Cosmology Telescope (ACT) from 2017 to 2021. In combination with BAO
measurements (from SDSS and 6dF), we obtain the amplitude of matter
fluctuations at 1.8% precision,
and the Hubble
constant at
1.6% precision. A joint constraint with CMB lensing measured by the Planck
satellite yields even more precise values: ,
and . These measurements agree
well with CDM-model extrapolations from the CMB anisotropies measured
by Planck. To compare these constraints to those from the KiDS, DES, and HSC
galaxy surveys, we revisit those data sets with a uniform set of assumptions,
and find from all three surveys are lower than that from ACT+Planck
lensing by varying levels ranging from 1.7-2.1. These results motivate
further measurements and comparison, not just between the CMB anisotropies and
galaxy lensing, but also between CMB lensing probing on
mostly-linear scales and galaxy lensing at on smaller scales. We
combine our CMB lensing measurements with CMB anisotropies to constrain
extensions of CDM, limiting the sum of the neutrino masses to eV (95% c.l.), for example. Our results provide independent
confirmation that the universe is spatially flat, conforms with general
relativity, and is described remarkably well by the CDM model, while
paving a promising path for neutrino physics with gravitational lensing from
upcoming ground-based CMB surveys.Comment: 30 pages, 16 figures, prepared for submission to ApJ. Cosmological
likelihood data is here:
https://lambda.gsfc.nasa.gov/product/act/actadv_prod_table.html ; likelihood
software is here: https://github.com/ACTCollaboration/act_dr6_lenslike . Also
see companion papers Qu et al and MacCrann et al. Mass maps will be released
when papers are publishe
The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth
We present new measurements of cosmic microwave background (CMB) lensing over
sq. deg. of the sky. These lensing measurements are derived from the
Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which
consists of five seasons of ACT CMB temperature and polarization observations.
We determine the amplitude of the CMB lensing power spectrum at
precision ( significance) using a novel pipeline that minimizes
sensitivity to foregrounds and to noise properties. To ensure our results are
robust, we analyze an extensive set of null tests, consistency tests, and
systematic error estimates and employ a blinded analysis framework. The
baseline spectrum is well fit by a lensing amplitude of
relative to the Planck 2018 CMB power spectra
best-fit CDM model and relative to
the best-fit model. From our lensing power
spectrum measurement, we derive constraints on the parameter combination
of
from ACT DR6 CMB lensing alone and
when combining ACT DR6 and Planck NPIPE
CMB lensing power spectra. These results are in excellent agreement with
CDM model constraints from Planck or
CMB power spectrum measurements. Our lensing measurements from redshifts
-- are thus fully consistent with CDM structure growth
predictions based on CMB anisotropies probing primarily . We find no
evidence for a suppression of the amplitude of cosmic structure at low
redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see
companion papers Madhavacheril et al and MacCrann et a
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