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- Trkulja, C. L., et al.
(author)
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Rational antibody design for undruggable targets using kinetically controlled biomolecular probes
- 2021
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:16
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Journal article (peer-reviewed)abstract
- Several important drug targets, e.g., ion channels and G protein-coupled receptors, are extremely difficult to approach with current antibody technologies. To address these targets classes, we explored kinetically controlled proteases as structural dynamics-sensitive druggability probes in native-state and disease-relevant proteins. By using low-Reynolds number flows, such that a single or a few protease incisions are made, we could identify antibody binding sites (epitopes) that were translated into short-sequence antigens for antibody production. We obtained molecular-level information of the epitope-paratope region and could produce high-affinity antibodies with programmed pharmacological function against difficult-to-drug targets. We demonstrate the first stimulus-selective monoclonal antibodies targeting the transient receptor potential vanilloid 1 (TRPV1) channel, a clinically validated pain target widely considered undruggable with antibodies, and apoptosis-inducing antibodies selectively mediating cytotoxicity in KRAS-mutated cells. It is our hope that this platform will widen the scope of antibody therapeutics for the benefit of patients.
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| 2. |
- De Silva, Amila O., et al.
(author)
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PFAS Exposure Pathways for Humans and Wildlife : A Synthesis of Current Knowledge and Key Gaps in Understanding
- 2021
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In: Environmental Toxicology and Chemistry. - : Pergamon Press. - 0730-7268 .- 1552-8618. ; 40:3, s. 631-657
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Research review (peer-reviewed)abstract
- Here we synthesize current understanding of the magnitudes and methods for assessing human and wildlife exposures to poly- and perfluoroalkyl substances (PFAS). Most human exposure assessments have focused on two to five legacy PFAS and wildlife assessments are typically limited to targeted PFAS (up to ~30 substances). However, shifts in chemical production are occurring rapidly and targeted methods for detecting PFAS have not kept pace with these changes. Total fluorine (TF) measurements complemented by suspect screening using high resolution mass spectrometry are thus emerging as essential tools for PFAS exposure assessment. Such methods enable researchers to better understand contributions from precursor compounds that degrade into terminal perfluoroalkyl acids (PFAA). Available data suggest that diet is the major human exposure pathway for some PFAS but there is large variability across populations and PFAS compounds. Additional data on TF in exposure media and the fraction of unidentified organofluorine are needed. Drinking water has been established as the major exposure source in contaminated communities. As water supplies are remediated, and for the general population, exposures from dust, personal care products, indoor environments and other sources may be more important. A major challenge for exposure assessments is the lack of statistically representative population surveys. For wildlife, bioaccumulation processes differ substantially between PFAS and neutral lipophilic organic compounds, prompting a revaluation of traditional bioaccumulation metrics. There is evidence that both phospholipids and proteins are important for the tissue partitioning and accumulation of PFAS. New mechanistic models for PFAS bioaccumulation are being developed that will assist in wildlife risk evaluations.
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| 4. |
- Saenger, A. K., et al.
(author)
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Multicenter analytical evaluation of a high-sensitivity troponin T assay
- 2011
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In: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 412:9-10, s. 748-754
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Journal article (peer-reviewed)abstract
- Background: High-sensitivity cardiac troponin assays are being introduced clinically for earlier diagnosis of acute myocardial infarction (AMI). We evaluated the analytical performance of a high-sensitivity cardiac troponin T assay (hscTnT. Roche Diagnostics) in a multicenter, international trial. Methods: Three US and 5 European sites evaluated hscTnT on the Modular (R) Analytics E170, cobas (R) 6000, Elecsys 2010, and cobas (R) e 411. Precision, accuracy, reportable range, an inter-laboratory comparison trial, and the 99th percentile of a reference population were assessed. Results: Total imprecision (CVs) were 4.6-36.8% between 3.4 and 10.3 ng/L hscTnT. Assay linearity was up to 10,000 ng/L and the limit of blank and detection were 3 and 5 ng/L, respectively. The 99th percentile reference limit was 14.2 ng/L (n = 533). No significant differences between specimen types, assay incubation time, or reagent lots existed. A substantial positive bias (76%) exists between the 4th generation and hscTnT assays at the low end of the measuring range (< 50 ng/L). hscTnT serum pool concentrations were within 2SD limits of the mean of means in the comparison trial, indicating comparable results across multiple platforms and laboratories. Conclusion: The Roche hscTnT assay conforms to guideline precision requirements and will likely identify additional patients with myocardial injury suspicious for AMI.
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| 8. |
- Bergstroem, Stig M., et al.
(author)
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Lower Katian (Upper Ordovician) delta(13)C chemostratigraphy, global correlation and sea-level changes in Baltoscandia
- 2011
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In: GFF. - : Informa UK Limited. - 2000-0863 .- 1103-5897. ; 133:1-2, s. 31-47
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Journal article (peer-reviewed)abstract
- A long-standing problem in the Ordovician stratigraphy of south-eastern Norway has been to the relations between the Mjosa Formation in the Lake Mjosa region and coeval strata in the Oslo region. The recent discovery of the globally distributed Guttenberg delta(13)C excursion (Guttenberg Isotopic Carbon Excursion) in the Mjosa region provided the impetus to search for this excellent chemostratigraphic marker in the classical Oslo region succession, where it was found in the Frognerkilen Formation. Another positive delta(13)C excursion, which we identify as the Kope excursion, was discovered in the Solvang Formation. The new data show that the lower Katian delta(13)C chemostratigraphy in the Oslo region is closely similar to that from south-eastern and southern Estonia. This permits detailed correlations across Baltoscandia, which are useful for recognising the Baltic stage boundaries in the Oslo region succession. Both the Lake Mjosa and Oslo regions study successions can be chemostratigraphically correlated with those in North America and eastern Asia. The newly established stratigraphic relations in the Oslo region are also used for a re-assessment of lower Katian local and eustatic sea-level changes.
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| 9. |
- Bergstroem, Stig M., et al.
(author)
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The delta C-13 chemostratigraphy of the Upper Ordovician Mjosa Formation at Furuberget near Hamar, southeastern Norway: Baltic, Trans-Atlantic, and Chinese relations
- 2010
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In: Norsk Geologisk Tidsskrift. - 1502-5322. ; 90:1-2, s. 65-78
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Journal article (peer-reviewed)abstract
- Whereas no studies have previously been carried out on the delta C-13 chemostratigraphy of the Sandbian-Katian (Upper Ordovician) succession anywhere in Norway, such investigations in Sweden and the East Baltic region have made the delta C-13 chemostratigraphy of that interval well known. 1 an attempt to document for the first time the presence of the globally distributed and stratigraphically important Guttenberg Carbon Isotope Excursion (GICE), 45 samples were collected at 2 m intervals through the Furnesfjorden and Galas members of the Mjosa Formation from two sections at Furuberget in the Nes-Hamar District 70 km north of the City of Oslo. Relatively high delta C-13 values, which are interpreted to represent the GICE, were obtained throughout the Galls Member. The presence of this delta C-13 excursion in the middle part of the Mjosa Formation, combined with biostratigraphic and other evidence, are used for detailed correlations of the Mjosa Formation with other successions in Baltoscandia, North America, and on the Yangtze Platform in southern China.
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| 10. |
- Bergström, Stig M., et al.
(author)
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Local and trans-Atlantic chemostratigraphic significance of new δ13Ccarb data from the Sandbian and Katian Stages (Middle–Upper Ordovician) of the Oslo region, Norway
- 2017
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In: GFF. - : Informa UK Limited. - 1103-5897 .- 2000-0863. ; 139:4, s. 289-300
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Journal article (peer-reviewed)abstract
- Late Sandbian to early Katian δ13Ccarb chemostratigraphy has in Norway been described in only two previous reports that dealt with two geographically rather widely separated areas, namely the Oslo-Asker district and the Nes-Hamar district. No data have been available from the Ordovician outcrop areas between these districts that could help clarify the partly unclear regional stratigraphic relations across the Oslo region. A chemostratigraphic study of the classical road section at Tønnerud in the northwestern Hadeland district about halfway between the previously investigated districts resulted in the recognition of two δ13C excursions, namely one in the uppermost Furuberget Formation tentatively identified as the Guttenberg Isotopic Carbon Excursion and one in the lower Solvang Formation that is classified as the KOPE (RAKVERE) excursion. Based on these results, the Furuberget and Solvang formations are interpreted to be separated by a significant gap in the study area corresponding to the Oandu and lower Rakvere regional Baltoscandic stages. This suggests that the Tønnerud succession is less complete stratigraphically than those in the Oslo-Asker district. Similar gaps are not uncommon in this interval in Baltoscandia and in North America and probably reflect both eustatic and local epeirogenetic movements that make it difficult to establish a regionally applicable sequence stratigraphy.
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