Opioids represent a highly-abused and highly potent class of drugs that have become a significant threat to public safety. Often there are little to no pharmacological and toxicological data ...available for new, illicitly used and abused opioids, and this has resulted in a growing number of serious adverse events, including death. The large influx of new synthetic opioids permeating the street-drug market, including fentanyl and fentanyl analogs, has generated the need for a fast and effective method to evaluate the risk a substance poses to public safety. In response, the US FDA's Center for Drug Evaluation and Research (CDER) has developed a rapidly-deployable, multi-pronged computational approach to assess a drug's risk to public health. A key component of this approach is a molecular docking model to predict the binding affinity of biologically uncharacterized fentanyl analogs to the mu opioid receptor. The model was validated by correlating the docking scores of structurally diverse opioids with experimentally determined binding affinities. Fentanyl derivatives with sub-nanomolar binding affinity at the mu receptor (e.g. carfentanil and lofentanil) have significantly lower binding scores, while less potent fentanyl derivatives have increased binding scores. The strong correlation between the binding scores and the experimental binding affinities suggests that this approach can be used to accurately predict the binding strength of newly identified fentanyl analogs at the mu receptor in the absence of in vitro data and may assist in the temporary scheduling of those substances that pose a risk to public safety.
Multispectral images of Mercury obtained by the MESSENGER spacecraft reveal that its surface has an overall relatively low reflectance with three large-scale units identified on the basis of ...reflectance and slope (0.4 to 1.0 micrometer). A higher-reflectance, relatively red material occurs as a distinct class of smooth plains that were likely emplaced volcanically; a lower-reflectance material with a lesser spectral slope may represent a distinct crustal component enriched in opaque minerals, possibly more common at depth. A spectrally intermediate terrain probably forms most of the upper crust. Three other spectrally distinct but spatially restricted units include fresh crater ejecta less affected by space weathering than other surface materials; high-reflectance deposits seen in some crater floors; and moderately high-reflectance, relatively reddish material associated with rimless depressions.
Evaluating kratom alkaloids using PHASE Ellis, Christopher R; Racz, Rebecca; Kruhlak, Naomi L ...
PloS one,
03/2020, Letnik:
15, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over ...forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.
Two-dimensional (2D) gel electrophoresis is a powerful technique enabling simultaneous visualization of relatively large portions of the proteome. However, the well documented issues of variation and ...lack of sensitivity and quantitative capabilities of existing labeling reagents, has limited the use of this technique as a quantitative tool. Two-dimensional difference gel electrophoresis (2D DIGE) builds on this technique by adding a highly accurate quantitative dimension. 2D DIGE enables multiple protein extracts to be separated on the same 2D gel. This is made possible by labeling of each extract using spectrally resolvable, size and charge-matched fluorescent dyes known as CyDye DIGE fluors. 2D DIGE involves use of a reference sample, known as an internal standard, which comprises equal amounts of all biological samples in the experiment. Including the internal standard on each gel in the experiment with the individual biological samples means that the abundance of each protein spot on a gel can be measured relative (i.e. as a ratio) to its corresponding spot in the internal standard present on the same gel. Ettan DIGE is the system of technologies that has been optimized to fully benefit from the advantages provided by 2D DIGE.
SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have ...been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful.
: Animal, in vitro and clinical data relevant to the biology of the renin-angiotensin system (RAS), its interaction with the kallikrein-kinin system (KKS) and SARS-CoV-2, and clinical studies were reviewed.
SARS-CoV-2 hijacks ACE2to invade and damage cells, downregulating ACE2, reducing its protective effects and exacerbating injurious Ang II effects. However, retrospective observational studies do not show higher risk of infection with ACEI or ARB use. Nevertheless, study of the RAS and KKS in the setting of coronaviral infection may yield therapeutic targets.
We present an overview of the operations, calibration, geodetic control, photometric standardization, and processing of images from the Mercury Dual Imaging System (MDIS) acquired during the orbital ...phase of the MESSENGER spacecraft’s mission at Mercury (18 March 2011–30 April 2015). We also provide a summary of all of the MDIS products that are available in NASA’s Planetary Data System (PDS). Updates to the radiometric calibration included slight modification of the frame-transfer smear correction, updates to the flat fields of some wide-angle camera (WAC) filters, a new model for the temperature dependence of narrow-angle camera (NAC) and WAC sensitivity, and an empirical correction for temporal changes in WAC responsivity. Further, efforts to characterize scattered light in the WAC system are described, along with a mosaic-dependent correction for scattered light that was derived for two regional mosaics. Updates to the geometric calibration focused on the focal lengths and distortions of the NAC and all WAC filters, NAC–WAC alignment, and calibration of the MDIS pivot angle and base. Additionally, two control networks were derived so that the majority of MDIS images can be co-registered with sub-pixel accuracy; the larger of the two control networks was also used to create a global digital elevation model. Finally, we describe the image processing and photometric standardization parameters used in the creation of the MDIS advanced products in the PDS, which include seven large-scale mosaics, numerous targeted local mosaics, and a set of digital elevation models ranging in scale from local to global.
The US Food and Drug Administration's Center for Drug Evaluation and Research (CDER) developed an investigational Public Health Assessment via Structural Evaluation (PHASE) methodology to provide a ...structure‐based evaluation of a newly identified opioid's risk to public safety. PHASE utilizes molecular structure to predict biological function. First, a similarity metric quantifies the structural similarity of a new drug relative to drugs currently controlled in the Controlled Substances Act (CSA). Next, software predictions provide the primary and secondary biological targets of the new drug. Finally, molecular docking estimates the binding affinity at the identified biological targets. The multicomponent computational approach coupled with expert review provides a rapid, systematic evaluation of a new drug in the absence of in vitro or in vivo data. The information provided by PHASE has the potential to inform law enforcement agencies with vital information regarding newly emerging illicit opioids.
There has only been one report thus far adding eye protection to universal masking, with no transmission to HCWs who added face shields in India during home visits 4. The goal of our study was to ...determine if frontline emergency clinicians contracted COVID-19 at a rate different from that predicted by community spread when implementing mandatory eye protection (in addition to masks). COVID-19 infection occurred among our frontline ED clinicians at a rate more comparable to community spread than to the prevalence in our ED patient population.
Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer therapy. Larger studies have shown ∼90% complete remission rates against chemoresistant and/or refractory ...CD19+ leukemia or lymphoma. Effective CAR T cell therapy is highly dependent on lymphodepleting preconditioning, which is achieved through chemotherapy or radiotherapy that carries with it significant toxicities. These can exclude patients of low performance status. In order to overcome the need for preconditioning, we constructed fully mouse first and second generation anti-murine CD19 CARs with or without interleukin-12 (IL-12) secretion. To test these CARs, we established a mouse model to reflect the human situation without preconditioning. Murine second generation CAR T cells expressing IL-12 were capable of eradicating established B cell lymphoma with a long-term survival rate of ∼25%. We believe this to be the first study in a truly lymphoreplete model. We provide evidence that IL-12-expressing CAR T cells not only directly kill target CD19+ cells, but also recruit host immune cells to an anti-cancer immune response. This finding is critical because lymphodepletion regimens required for the success of current CAR T cell technology eliminate host immune cells whose anti-cancer activity could otherwise be harnessed by strategies such as IL-12-secreting CAR T cells.
The Mercury Dual Imaging System (MDIS) on the MESSENGER spacecraft will provide critical measurements tracing Mercury's origin and evolution. MDIS consists of a monochrome narrow-angle camera (NAC) ...and a multispectral wide-angle camera (WAC). The NAC is a 1.5 degree field-of-view (FOV) off-axis reflector, coaligned with the WAC, a four-element refractor with a 10.5 degree FOV and 12-color filter wheel. The focal plane electronics of each camera are identical and use a 1,024 x 1,024 Atmel (Thomson) TH7888A charge-coupled device detector. Only one camera operates at a time, allowing them to share a common set of control electronics. The NAC and the WAC are mounted on a pivoting platform that provides a 90 degree field-of-regard, extending 40 degree sunward and 50 degree anti-sunward from the spacecraft +Z-axis-the boresight direction of most of MESSENGER's instruments. Onboard data compression provides capabilities for pixel binning, remapping of 12-bit data into 8 bits, and lossless or lossy compression. MDIS will acquire four main data sets at Mercury during three flybys and the two-Mercury-solar-day nominal mission: a monochrome global image mosaic at near-zero emission angles and moderate incidence angles, a stereo-complement map at off-nadir geometry and near-identical lighting, multicolor images at low incidence angles, and targeted high-resolution images of key surface features. These data will be used to construct a global image base map, a digital terrain model, global maps of color properties, and mosaics of high-resolution image strips. Analysis of these data will provide information on Mercury's impact history, tectonic processes, the composition and emplacement history of volcanic materials, and the thickness distribution and compositional variations of crustal materials. This paper summarizes MDIS's science objectives and technical design, including the common payload design of the MDIS data processing units, as well as detailed results from ground and early flight calibrations and plans for Mercury image products to be generated from MDIS data.
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