171 research outputs found
The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model
Author Posting. © American Chemical Society, 2020. This is an open access article published under an ACS AuthorChoice License. The definitive version was published in Chemical Research in Toxicology, 33(4), (2020): 860-879, doi:10.1021/acs.chemrestox.9b00476.The Ah receptor (AHR) has been studied for almost five decades. Yet, we still have many important questions about its role in normal physiology and development. Moreover, we still do not fully understand how this protein mediates the adverse effects of a variety of environmental pollutants, such as the polycyclic aromatic hydrocarbons (PAHs), the chlorinated dibenzo-p-dioxins (âdioxinsâ), and many polyhalogenated biphenyls. To provide a platform for future research, we provide the historical underpinnings of our current state of knowledge about AHR signal transduction, identify a few areas of needed research, and then develop concepts such as adaptive metabolism, ligand structural diversity, and the importance of proligands in receptor activation. We finish with a discussion of the cognate physiological role of the AHR, our perspective on why this receptor is so highly conserved, and how we might think about its cognate ligands in the future.This review is dedicated in memory of the career of Alan Poland, one of the truly great minds in pharmacology and toxicology. This work was supported by the National Institutes of Health Grants R35-ES028377, T32-ES007015, P30-CA014520, P42-ES007381, and U01-ES1026127, The UW SciMed GRS Program, and The Morgridge Foundation. The authors would like to thank Catherine Stanley of UW Media Solutions for her artwork
Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution
Conformation
and dynamics of the vasoconstrictive peptides human
urotensin II (UII) and urotensin related peptide (URP) have been investigated
by both unrestrained and enhanced-sampling molecular-dynamics (MD)
simulations and NMR spectroscopy. These peptides are natural ligands
of the G-protein coupled urotensin II receptor (UTR) and have been
linked to mammalian pathophysiology. UII and URP cannot be characterized
by a single structure but exist as an equilibrium of two main classes
of ring conformations, <i>open</i> and <i>folded</i>, with rapidly interchanging subtypes. The <i>open</i> states
are characterized by turns of various types centered at K<sup>8</sup>Y<sup>9</sup> or F<sup>6</sup>W<sup>7</sup> predominantly with no
or only sparsely populated transannular hydrogen bonds. The <i>folded</i> conformations show multiple turns stabilized by highly
populated transannular hydrogen bonds comprising centers F<sup>6</sup>W<sup>7</sup>K<sup>8</sup> or W<sup>7</sup>K<sup>8</sup>Y<sup>9</sup>. Some of these conformations have not been characterized previously.
The equilibrium populations that are experimentally difficult to access
were estimated by replica-exchange MD simulations and validated by
comparison of experimental NMR data with chemical shifts calculated
with density-functional theory. UII exhibits approximately 72% <i>open</i>:28% <i>folded</i> conformations in aqueous
solution. URP shows very similar ring conformations as UII but differs
in an <i>open:folded</i> equilibrium shifted further toward <i>open</i> conformations (86:14) possibly arising from the absence
of folded N-terminal tail-ring interaction. The results suggest that
the different biological effects of UII and URP are not caused by
differences in ring conformations but rather by different interactions
with UTR
Recommended from our members
2018 Proceedings of the International Conference on Trauma Surgery Technology in Giessen
The overarching goal of the gathering was to define a concept for technology design research in Giessen to improve patient outcomes through the design of assistive technology that assists both patients and surgeons. The emerging field of regenerative rehabilitation where trauma patients are treated by methods of regenerative medicine promises great improvements for our field, but clinical success is yet to be realised. The symposium was specifically organised to acknowledge and address these issues
Early mobilization in the critical care unit: A review of adult and pediatric literature.
Early mobilization of critically ill patients is beneficial, suggesting that it should be incorporated into daily clinical practice. Early passive, active, and combined progressive mobilizations can be safely initiated in intensive care units (ICUs). Adult patients receiving early mobilization have fewer ventilator-dependent days, shorter ICU and hospital stays, and better functional outcomes. Pediatric ICU data are limited, but recent studies also suggest that early mobilization is achievable without increasing patient risk. In this review, we provide a current and comprehensive appraisal of ICU mobilization techniques in both adult and pediatric critically ill patients. Contraindications and perceived barriers to early mobilization, including cost and health care provider views, are identified. Methods of overcoming barriers to early mobilization and enhancing sustainability of mobilization programs are discussed. Optimization of patient outcomes will require further studies on mobilization timing and intensity, particularly within specific ICU populations
Recommended from our members
Co-variation of crenarchaeol and branched GDGTs in globally-distributed marine and freshwater sedimentary archives
Two major types of glycerol dialkyl glycerol tetraethers (GDGTs) are commonly
used in paleoecological and paleoclimatological reconstructions: isoprenoidal and
branched GDGTs. In aquatic environments, it was originally assumed that isoprenoidal
GDGTs, especially crenarchaeol, derive mainly from aquatic Thaumarchaeota, whilst
branched GDGTs are an allochthonous input derived from soil Bacteria. Recently,
direct co-variation of crenarchaeol and branched GDGTs has been described in two
marine sedimentary records, and this observation suggests in situ production of
branched GDGTs is possible at least in some aquatic environments. After investigating
30 published and unpublished data sets from downcore and surface sediments as well as
sediment traps from 19 distinct regions around the world, we found a widespread
significant correlation between concentrations of branched GDGTs and crenarchaeol
(p<0.01; rÂČ=0.57-0.99), even when normalized against TOC, where available. These
data sets include freshwater and marine environments with varying distances from the
shore, varying redox conditions and different terrestrial matter input pathways. Our
findings from this large-scale data set suggest that a common or mixed source for both
GDGT types is actually commonplace in lacustrine and marine settings.Keywords: Branched GDGTs,
Oceans,
Crenarchaeol,
Archaea,
Isoprenoid GDGTs,
Lakes,
In situ production
Polyfunctional Type-1, -2, and -17 CD8+ T Cell Responses to Apoptotic Self-Antigens Correlate with the Chronic Evolution of Hepatitis C Virus Infection
Caspase-dependent cleavage of antigens associated with apoptotic cells plays a prominent role in the generation of CD8+ T cell responses in various infectious diseases. We found that the emergence of a large population of autoreactive CD8+ T effector cells specific for apoptotic T cell-associated self-epitopes exceeds the antiviral responses in patients with acute hepatitis C virus infection. Importantly, they endow mixed polyfunctional type-1, type-2 and type-17 responses and correlate with the chronic progression of infection. This evolution is related to the selection of autoreactive CD8+ T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction in patients who clear infection. These findings demonstrate a previously undescribed strict link between the emergence of high frequencies of mixed autoreactive CD8+ T cells producing a broad array of cytokines (IFN-Îł, IL-17, IL-4, IL-2âŠ) and the progression toward chronic disease in a human model of acute infection
The large area detector onboard the eXTP mission
The Large Area Detector (LAD) is the high-throughput, spectral-timing instrument onboard the eXTP mission, a flagship
mission of the Chinese Academy of Sciences and the China National Space Administration, with a large European
participation coordinated by Italy and Spain. The eXTP mission is currently performing its phase B study, with a target
launch at the end-2027. The eXTP scientific payload includes four instruments (SFA, PFA, LAD and WFM) offering
unprecedented simultaneous wide-band X-ray timing and polarimetry sensitivity. The LAD instrument is based on the
design originally proposed for the LOFT mission. It envisages a deployed 3.2 m2 effective area in the 2-30 keV energy
range, achieved through the technology of the large-area Silicon Drift Detectors - offering a spectral resolution of up to
200 eV FWHM at 6 keV - and of capillary plate collimators - limiting the field of view to about 1 degree. In this paper
we will provide an overview of the LAD instrument design, its current status of development and anticipated
performance
Report from Working Group 3: Beyond the standard model physics at the HL-LHC and HE-LHC
This is the third out of five chapters of the final report [1] of the Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to the study of the potential, in the search for Beyond the Standard Model (BSM) physics, of the High Luminosity (HL) phase of the LHC, defined as ab of data taken at a centre-of-mass energy of 14 TeV, and of a possible future upgrade, the High Energy (HE) LHC, defined as ab of data at a centre-of-mass energy of 27 TeV. We consider a large variety of new physics models, both in a simplified model fashion and in a more model-dependent one. A long list of contributions from the theory and experimental (ATLAS, CMS, LHCb) communities have been collected and merged together to give a complete, wide, and consistent view of future prospects for BSM physics at the considered colliders. On top of the usual standard candles, such as supersymmetric simplified models and resonances, considered for the evaluation of future collider potentials, this report contains results on dark matter and dark sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like particles, heavy scalars, vector-like quarks, and more. Particular attention is placed, especially in the study of the HL-LHC prospects, to the detector upgrades, the assessment of the future systematic uncertainties, and new experimental techniques. The general conclusion is that the HL-LHC, on top of allowing to extend the present LHC mass and coupling reach by on most new physics scenarios, will also be able to constrain, and potentially discover, new physics that is presently unconstrained. Moreover, compared to the HL-LHC, the reach in most observables will, generally more than double at the HE-LHC, which may represent a good candidate future facility for a final test of TeV-scale new physics
The United States COVID-19 Forecast Hub dataset
Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages
Towards a muon collider
A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work
- âŠ