| 1. |
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| 2. |
- Giacomini, L., et al.
(author)
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Geologic mapping of the Comet 67P/Churyumov-Gerasimenko's Northern hemisphere
- 2016
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 462, s. S352-S369
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Journal article (peer-reviewed)abstract
- The Optical, Spectroscopic, and Infrared Remote Imaging System (OSIRIS), the scientific imaging system onboard the Rosetta mission, has been acquiring images of the nucleus of the comet 67P/Churyumov-Gerasimenko since 2014 August with a resolution which allows a detailed analysis of its surface. Indeed, data reveal a complex surface morphology which is likely the expression of different processes which occurred at different times on the cometary nucleus. In order to characterize these different morphologies and better understand their distribution, we performed a geologic mapping of comet's 67P Northern hemisphere in which features have been distinguished based on their morphological, textural and stratigraphic characteristics. For this purpose, we used narrow-angle camera images acquired in 2014 August and September with a spatial scale ranging from 1.2 to 2.4 m pixel(-1). Several different geologic units have been identified on the basis of their different surface textures, granulometry and morphology. Some of these units are distinctive and localized, whereas others are more common and distributed all over the Northern hemisphere. Moreover, different types of linear features have been distinguished on the basis of their morphology. Some of these lineaments have never been observed before on a comet and can offer important clues on the internal structures of the nucleus itself. The geologic mapping results presented here will allow us to better understand the processes which affected the nucleus' surface and thus the origin and evolutionary history of comet 67P/Churyumov-Gerasimenko.
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| 3. |
- Thomas, N., et al.
(author)
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Redistribution of particles across the nucleus of comet 67P/Churyumov-Gerasimenko
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 583
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Journal article (peer-reviewed)abstract
- Context. We present an investigation of the surface properties of areas on the nucleus of comet 67P/Churyumov-Gerasimenko. Aims. We aim to show that transport of material from one part of the cometary nucleus to another is a significant mechanism that influences the appearance of the nucleus and the surface thermal properties. Methods. We used data from the OSIRIS imaging system onboard the Rosetta spacecraft to identify surface features on the nucleus that can be produced by various transport mechanisms. We used simple calculations based on previous works to establish the plausibility of dust transport from one part of the nucleus to another. Results. We show by observation and modeling that "airfall" as a consequence of non-escaping large particles emitted from the neck region of the nucleus is a plausible explanation for the smooth thin deposits in the northern hemisphere of the nucleus. The consequences are also discussed. We also present observations of aeolian ripples and ventifacts. We show by numerical modeling that a type of saltation is plausible even under the rarified gas densities seen at the surface of the nucleus. However, interparticle cohesive forces present difficulties for this model, and an alternative mechanism for the initiation of reptation and creep may result from the airfall mechanism. The requirements on gas density and other parameters of this alternative make it a more attractive explanation for the observations. The uncertainties and implications are discussed.
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| 4. |
- El-Maarry, M. R., et al.
(author)
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Regional surface morphology of comet 67P/Churyumov-Gerasimenko from Rosetta/OSIRIS images
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 583
-
Journal article (peer-reviewed)abstract
- Aims. The OSIRIS camera onboard the Rosetta spacecraft has been acquiring images of the comet 67P/Churyumov-Gerasimenko (67P)'s nucleus at spatial resolutions down to similar to 0.17 m/px ever since Aug. 2014. These images have yielded unprecedented insight into the morphological diversity of the comet's surface. This paper presents an overview of the regional morphology of comet 67P. Methods. We used the images that were acquired at orbits similar to 20-30 km from the center of the comet to distinguish different regions on the surface and introduce the basic regional nomenclature adopted by all papers in this Rosetta special feature that address the comet's morphology and surface processes. We used anaglyphs to detect subtle regional and topographical boundaries and images from close orbit (similar to 10 km from the comet's center) to investigate the fine texture of the surface. Results. Nineteen regions have currently been defined on the nucleus based on morphological and/or structural boundaries, and they can be grouped into distinctive region types. Consolidated, fractured regions are the most common region type. Some of these regions enclose smooth units that appear to settle in gravitational sinks or topographically low areas. Both comet lobes have a significant portion of their surface covered by a dusty coating that appears to be recently placed and shows signs of mobilization by aeolian-like processes. The dusty coatings cover most of the regions on the surface but are notably absent from a couple of irregular large depressions that show sharp contacts with their surroundings and talus-like deposits in their interiors, which suggests that short-term explosive activity may play a significant role in shaping the comet's surface in addition to long-term sublimation loss. Finally, the presence of layered brittle units showing signs of mechanical failure predominantly in one of the comet's lobes can indicate a compositional heterogeneity between the two lobes.
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| 5. |
- El-Marry, M. R., et al.
(author)
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Regional surface morphology of comet 67P/Churyumov-Gerasimenko from Rosetta/OSIRIS images : The southern hemisphere
- 2016
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 593
-
Journal article (peer-reviewed)abstract
- Aims. The OSIRIS camera on board the Rosetta spacecraft has been acquiring images of the comet 67P/Churyumov-Gerasimenko (67P)'s nucleus since August 2014. Starting in May 2015, the southern hemisphere gradually became illuminated and was imaged for the first time. Here we present the regional morphology of the southern hemisphere, which serves as a companion to an earlier paper that presented the regional morphology of the northern hemisphere. Methods. We used OSIRIS images that were acquired at orbits similar to 45-125 km from the center of the comet (corresponding to spatial resolutions of similar to 0.8 to 2.3 m/pixel) coupled with the use of digital terrain models to define the different regions on the surface, and identify structural boundaries accurately. Results. Seven regions have been defined in the southern hemisphere bringing the total number of defined regions on the surface of the nucleus to 26. These classifications are mainly based on morphological and/or topographic boundaries. The southern hemisphere shows a remarkable dichotomy with its northern counterpart mainly because of the absence of wide-scale smooth terrains, dust coatings and large unambiguous depressions. As a result, the southern hemisphere closely resembles previously identified consolidated regions. An assessment of the overall morphology of comet 67P suggests that the comet's two lobes show surface heterogeneities manifested in different physical/mechanical characteristics, possibly extending to local (i.e., within a single region) scales.
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| 6. |
- Fornasier, S., et al.
(author)
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The highly active Anhur-Bes regions in the 67P/Churyumov-Gerasimenko comet : results from OSIRIS/ROSETTA observations
- 2017
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In: Monthly notices of the Royal Astronomical Society. - : OXFORD UNIV PRESS. - 0035-8711 .- 1365-2966. ; 469, s. S93-S107
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Journal article (peer-reviewed)abstract
- The Southern hemisphere of the 67P/Churyumov-Gerasimenko comet has become visible from Rosetta only since 2015 March. It was illuminated during the perihelion passage and therefore it contains the regions that experienced the strongest heating and erosion rates, thus exposing the sub-surface most pristine material. In this work we investigate, thanks to the OSIRIS images, the geomorphology, the spectrophotometry and some transient events of two Southern hemisphere regions: Anhur and part of Bes. Bes is dominated by outcropping consolidated terrain covered with fine particle deposits, while Anhur appears strongly eroded with elongated canyon-like structures, scarp retreats, different kinds of deposits and degraded sequences of strata indicating a pervasive layering. We discovered a new 140 m long and 10 m high scarp formed in the Anhur-Bes boundary during/after the perihelion passage, close to the area where exposed CO2 and H2O ices were previously detected. Several jets have been observed originating from these regions, including the strong perihelion outburst, an active pit and a faint optically thick dust plume. We identify several areas with a relatively bluer slope (i.e. a lower spectral slope value) than their surroundings, indicating a surface composition enriched with some water ice. These spectrally bluer areas are observed especially in talus and gravitational accumulation deposits where freshly exposed material had fallen from nearby scarps and cliffs. The investigated regions become spectrally redder beyond 2 au outbound when the dust mantle became thicker, masking the underlying ice-rich layers.
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| 7. |
- Bertini, I., et al.
(author)
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Search for satellites near comet 67P/Churyumov-Gerasimenko using Rosetta/OSIRIS images
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 583
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Journal article (peer-reviewed)abstract
- Context. The European Space Agency Rosetta mission reached and started escorting its main target, the Jupiter-family comet 67P/Churyumov-Gerasimenko, at the beginning of August 2014. Within the context of solar system small bodies, satellite searches from approaching spacecraft were extensively used in the past to study the nature of the visited bodies and their collisional environment. Aims. During the approaching phase to the comet in July 2014, the OSIRIS instrument onboard Rosetta performed a campaign aimed at detecting objects in the vicinity of the comet nucleus and at measuring these objects' possible bound orbits. In addition to the scientific purpose, the search also focused on spacecraft security to avoid hazardous material in the comet's environment. Methods. Images in the red spectral domain were acquired with the OSIRIS Narrow Angle Camera, when the spacecraft was at a distance between 5785 km and 5463 km to the comet, following an observational strategy tailored to maximize the scientific outcome. From the acquired images, sources were extracted and displayed to search for plausible displacements of all sources from image to image. After stars were identified, the remaining sources were thoroughly analyzed. To place constraints on the expected displacements of a potential satellite, we performed Monte Carlo simulations on the apparent motion of potential satellites within the Hill sphere. Results. We found no unambiguous detections of objects larger than similar to 6 m within similar to 20 km and larger than similar to 1 m between similar to 20 km and similar to 110 km from the nucleus, using images with an exposure time of 0.14 s and 1.36 s, respectively. Our conclusions are consistent with independent works on dust grains in the comet coma and on boulders counting on the nucleus surface. Moreover, our analysis shows that the comet outburst detected at the end of April 2014 was not strong enough to eject large objects and to place them into a stable orbit around the nucleus. Our findings underline that it is highly unlikely that large objects survive for a long time around cometary nuclei.
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| 8. |
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| 9. |
- La Forgia, F., et al.
(author)
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Geomorphology and spectrophotometry of Philae's landing site on comet 67P/Churyumov-Gerasimenko
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 583
-
Journal article (peer-reviewed)abstract
- Context. On 12 November 2014 the European mission Rosetta succeeded in delivering a lander, named Philae, on the surface of one of the smallest, low-gravity and most primitive bodies of the solar system, the comet 67P/Churyumov-Gerasimenko (67P). Aims. The aim of this paper is to provide a comprehensive geomorphological and spectrophotometric analysis of Philae's landing site (Agilkia) to give an essential framework for the interpretation of its in situ measurements. Methods. OSIRIS images, coupled with gravitational slopes derived from the 3D shape model based on stereo-photogrammetry were used to interpret the geomorphology of the site. We adopted the Hapke model, using previously derived parameters, to photometrically correct the images in orange filter (649.2 nm). The best approximation to the Hapke model, given by the Akimov parameter-less function, was used to correct the reflectance for the effects of viewing and illumination conditions in the other filters. Spectral analyses on coregistered color cubes were used to retrieve spectrophotometric properties. Results. The landing site shows an average normal albedo of 6.7% in the orange filter with variations of similar to 15% and a global featureless spectrum with an average red spectral slope of 15.2%/100 nm between 480.7 nm (blue filter) and 882.1 nm (near-IR filter). The spatial analysis shows a well-established correlation between the geomorphological units and the photometric characteristics of the surface. In particular, smooth deposits have the highest reflectance a bluer spectrum than the outcropping material across the area. Conclusions. The featureless spectrum and the redness of the material are compatible with the results by other instruments that have suggested an organic composition. The observed small spectral variegation could be due to grain size effects. However, the combination of photometric and spectral variegation suggests that a compositional differentiation is more likely. This might be tentatively interpreted as the effect of the efficient dust-transport processes acting on 67P. High-activity regions might be the original sources for smooth fine-grained materials that then covered Agilkia as a consequence of airfall of residual material. More observations performed by OSIRIS as the comet approaches the Sun would help interpreting the processes that work at shaping the landing site and the overall nucleus.
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| 10. |
- Giacomini, K. M., et al.
(author)
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New and Emerging Research on Solute Carrier and ATP Binding Cassette Transporters in Drug Discovery and Development: Outlook from the International Transporter Consortium
- 2022
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In: Clinical Pharmacology & Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 112:3, s. 540-561
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Journal article (peer-reviewed)abstract
- Enabled by a plethora of new technologies, research in membrane transporters has exploded in the past decade. The goal of this state-of-the-art article is to describe recent advances in research on membrane transporters that are particularly relevant to drug discovery and development. This review covers advances in basic, translational, and clinical research that has led to an increased understanding of membrane transporters at all levels. At the basic level, we describe the available crystal structures of membrane transporters in both the solute carrier (SLC) and ATP binding cassette superfamilies, which has been enabled by the development of cryogenic electron microscopy methods. Next, we describe new research on lysosomal and mitochondrial transporters as well as recently deorphaned transporters in the SLC superfamily. The translational section includes a summary of proteomic research, which has led to a quantitative understanding of transporter levels in various cell types and tissues and new methods to modulate transporter function, such as allosteric modulators and targeted protein degraders of transporters. The section ends with a review of the effect of the gut microbiome on modulation of transporter function followed by a presentation of 3D cell cultures, which may enable in vivo predictions of transporter function. In the clinical section, we describe new genomic and pharmacogenomic research, highlighting important polymorphisms in transporters that are clinically relevant to many drugs. Finally, we describe new clinical tools, which are becoming increasingly available to enable precision medicine, with the application of tissue-derived small extracellular vesicles and real-world biomarkers.
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| 11. |
- Ahlin, Gustav, 1977-, et al.
(author)
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Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: : predictions of metformin interactions
- 2011
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In: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 11:6, s. 400-411
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Journal article (peer-reviewed)abstract
- Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human OCT1-reference or the variants R61C, V408M, M420del and G465R were first used to study the kinetics and inhibition pattern of the OCT1 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP(+)). In the second part OCT1-mediated (14)C-metformin uptake was studied in the presence of drugs administered concomitantly with metformin. Transport studies using ASP(+) showed that the function of the variants decreased in the following order: OCT1-reference = V408M = M420del >R61C > >G465R. Variants M420del and R61C were more sensitive to drug inhibition, with IC(50) values up to 23 times lower than those of the OCT1-reference. Uptake studies using (14)C-metformin were in qualitative agreement with those using ASP(+), with the exception that a larger reduction in transport capacity was observed for M420del. Concomitantly administered drugs, such as verapamil and amitriptyline, revealed potential drug-drug interactions at clinical plasma concentrations of metformin for OCT1-M420del.
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| 12. |
- Codenotti, S, et al.
(author)
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Hyperactive Akt1 Signaling Increases Tumor Progression and DNA Repair in Embryonal Rhabdomyosarcoma RD Line and Confers Susceptibility to Glycolysis and Mevalonate Pathway Inhibitors
- 2022
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In: Cells. - : MDPI AG. - 2073-4409. ; 11:18
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Journal article (peer-reviewed)abstract
- In pediatric rhabdomyosarcoma (RMS), elevated Akt signaling is associated with increased malignancy. Here, we report that expression of a constitutively active, myristoylated form of Akt1 (myrAkt1) in human RMS RD cells led to hyperactivation of the mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) pathway, resulting in the loss of both MyoD and myogenic capacity, and an increase of Ki67 expression due to high cell mitosis. MyrAkt1 signaling increased migratory and invasive cell traits, as detected by wound healing, zymography, and xenograft zebrafish assays, and promoted repair of DNA damage after radiotherapy and doxorubicin treatments, as revealed by nuclear detection of phosphorylated H2A histone family member X (γH2AX) through activation of DNA-dependent protein kinase (DNA-PK). Treatment with synthetic inhibitors of phosphatidylinositol-3-kinase (PI3K) and Akt was sufficient to completely revert the aggressive cell phenotype, while the mTOR inhibitor rapamycin failed to block cell dissemination. Furthermore, we found that pronounced Akt1 signaling increased the susceptibility to cell apoptosis after treatments with 2-deoxy-D-glucose (2-DG) and lovastatin, enzymatic inhibitors of hexokinase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), especially in combination with radiotherapy and doxorubicin. In conclusion, these data suggest that restriction of glucose metabolism and the mevalonate pathway, in combination with standard therapy, may increase therapy success in RMS tumors characterized by a dysregulated Akt signaling.
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| 13. |
- Li, Josephine H., et al.
(author)
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Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
- 2023
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:8, s. 1161-1172
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Journal article (peer-reviewed)abstract
- Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been repli-cated in the Diabetes Prevention Program (DPP). To as-sess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal compo-nents. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes inci-dence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 1029). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, b = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10212). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, b = 27.55 [95% CI 29.88, 25.22]; P = 3.2 × 10210) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 1024 ]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Galetin, Aleksandra, et al.
(author)
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Membrane transporters in drug development and as determinants of precision medicine
- 2024
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In: NATURE REVIEWS DRUG DISCOVERY. - 1474-1776 .- 1474-1784.
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Research review (peer-reviewed)abstract
- The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions. Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.
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| 18. |
- Hesselson, Stephanie E, et al.
(author)
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Genetic variation in the proximal promoter of ABC and SLC superfamilies : liver and kidney specific expression and promoter activity predict variation
- 2009
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:9, s. e6942-
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Journal article (peer-reviewed)abstract
- Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (pi) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.
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| 19. |
- Matsson, Pär, et al.
(author)
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Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping
- 2012
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In: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 12, s. 214-226
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Journal article (peer-reviewed)abstract
- ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.
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| 20. |
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| 21. |
- Sierks, Holger, et al.
(author)
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On the nucleus structure and activity of comet 67P/Churyumov-Gerasimenko
- 2015
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6220
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Journal article (peer-reviewed)abstract
- Images from the OSIRIS scientific imaging system onboard Rosetta show that the nucleus of 67P/Churyumov-Gerasimenko consists of two lobes connected by a short neck. The nucleus has a bulk density less than half that of water. Activity at a distance from the Sun of >3 astronomical units is predominantly from the neck, where jets have been seen consistently. The nucleus rotates about the principal axis of momentum. The surface morphology suggests that the removal of larger volumes of material, possibly via explosive release of subsurface pressure or via creation of overhangs by sublimation, may be a major mass loss process. The shape raises the question of whether the two lobes represent a contact binary formed 4.5 billion years ago, or a single body where a gap has evolved via mass loss.
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| 22. |
- Thomas, Nicolas, et al.
(author)
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The morphological diversity of comet 67P/Churyumov-Gerasimenko
- 2015
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6220
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Journal article (peer-reviewed)abstract
- Images of comet 67P/Churyumov-Gerasimenko acquired by the OSIRIS (Optical, Spectroscopic and Infrared Remote Imaging System) imaging system onboard the European Space Agency's Rosetta spacecraft at scales of better than 0.8 meter per pixel show a wide variety of different structures and textures. The data show the importance of airfall, surface dust transport, mass wasting, and insolation weathering for cometary surface evolution, and they offer some support for subsurface fluidization models and mass loss through the ejection of large chunks of material.
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| 23. |
- Yee, Sook Wah, et al.
(author)
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Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.
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| 24. |
- Yee, Sook Wah, et al.
(author)
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The full spectrum of OCT1 (SLC22A1) mutations bridges transporter biophysics to drug pharmacogenomics
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Other publication (other academic/artistic)abstract
- Membrane transporters play a fundamental role in the tissue distribution of endogenous compounds and xenobiotics and are major determinants of efficacy and side effects profiles. Polymorphisms within these drug transporters result in inter-individual variation in drug response, with some patients not responding to the recommended dosage of drug whereas others experience catastrophic side effects. For example, variants within the major hepatic Human organic cation transporter OCT1 (SLC22A1) can change endogenous organic cations and many prescription drug levels. To understand how variants mechanistically impact drug uptake, we systematically study how all known and possible single missense and single amino acid deletion variants impact expression and substrate uptake of OCT1. We find that human variants primarily disrupt function via folding rather than substrate uptake. Our study revealed that the major determinants of folding reside in the first 300 amino acids, including the first 6 transmembrane domains and the extracellular domain (ECD) with a stabilizing and highly conserved stabilizing helical motif making key interactions between the ECD and transmembrane domains. Using the functional data combined with computational approaches, we determine and validate a structure-function model of OCT1s conformational ensemble without experimental structures. Using this model and molecular dynamic simulations of key mutants, we determine biophysical mechanisms for how specific human variants alter transport phenotypes. We identify differences in frequencies of reduced function alleles across populations with East Asians vs European populations having the lowest and highest frequency of reduced function variants, respectively. Mining human population databases reveals that reduced function alleles of OCT1 identified in this study associate significantly with high LDL cholesterol levels. Our general approach broadly applied could transform the landscape of precision medicine by producing a mechanistic basis for understanding the effects of human mutations on disease and drug response.
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| 25. |
- Yee, Sook Wah, et al.
(author)
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The full spectrum of SLC22 OCT1 mutations illuminates the bridge between drug transporter biophysics and pharmacogenomics
- 2024
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In: Molecular Cell. - : Cell Press. - 1097-2765 .- 1097-4164. ; 84:10, s. 10-1932
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Journal article (peer-reviewed)abstract
- Mutations in transporters can impact an individual's response to drugs and cause many diseases. Few variants in transporters have been evaluated for their functional impact. Here, we combine saturation mutagenesis and multi-phenotypic screening to dissect the impact of 11,213 missense single-amino-acid deletions, and synonymous variants across the 554 residues of OCT1, a key liver xenobiotic transporter. By quantifying in parallel expression and substrate uptake, we find that most variants exert their primary effect on protein abundance, a phenotype not commonly measured alongside function. Using our mutagenesis results combined with structure prediction and molecular dynamic simulations, we develop accurate structure-function models of the entire transport cycle, providing biophysical characterization of all known and possible human OCT1 polymorphisms. This work provides a complete functional map of OCT1 variants along with a framework for integrating functional genomics, biophysical modeling, and human genetics to predict variant effects on disease and drug efficacy.
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| 26. |
- Zou, L., et al.
(author)
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Drug Metabolites Potently Inhibit Renal Organic Anion Transporters, OAT1 and OAT3
- 2021
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549. ; 110:1, s. 347-353
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Journal article (peer-reviewed)abstract
- Human OAT1 and OAT3 play major roles in renal drug elimination and drug-drug interactions. However, there is little information on the interactions of drug metabolites with transporters. The goal of this study was to characterize the interactions of drug metabolites with OAT1 and OAT3 and compare their potencies of inhibition with those of their corresponding parent drugs. Using HEK293 cells stably transfected with OAT1 and OAT3, 25 drug metabolites and their corresponding parent drugs were screened for inhibitory effects on OAT1-and OAT3-mediated 6-carboxyfluorescein uptake at a screening concentration of 200 mu M for all but 3 compounds. 20 and 24 drug metabolites were identified as inhibitors (inhibition > 50%) of OAT1 and OAT3, respectively. Seven drug metabolites were potent inhibitors of either or both OAT1 and OAT3 with K-i values less than 1 mu M. 22 metabolites were more potent inhibitors of OAT3 than OAT1. Importantly, one drug and four metabolites were predicted to inhibit OAT3 at unbound plasma concentrations achieved clinically (C-max,C-u/K-i values >= 0.1). In conclusion, our study highlights the potential interactions of drug metabolites with OAT1 and OAT3 at clinically relevant concentrations, suggesting that drug metabolites may modulate therapeutic and adverse drug response by inhibiting renal drug transporters. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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