| 1. |
- 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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| 11. |
- Bruton, Joseph D., et al.
(author)
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Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion
- 2003
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In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 17:2, s. 301-303
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Journal article (peer-reviewed)abstract
- The ryanodine (RY) receptors in beta-cells amplify signals by Ca2+-induced Ca2+ release (CICR). The role of CICR in insulin secretion remains unclear in spite of the fact that caffeine is known to stimulate secretion. This effect of caffeine is attributed solely to the inhibition of cAMP-phosphodiesterases (cAMP-PDEs). We demonstrate that stimulation of insulin secretion by caffeine is due to a sensitization of the RY receptors. The dose-response relationship of caffeine-induced inhibition of cAMP-PDEs was not correlated with the stimulation of insulin secretion. Sensitization of the RY receptors stimulated insulin secretion in a context-dependent manner, that is, only in the presence of a high concentration of glucose. This effect of caffeine depended on an increase in [Ca2+]i. Confocal images of beta-cells demonstrated an increase in [Ca2+]i induced by caffeine but not by forskolin. 9-Methyl-7-bromoeudistomin D (MBED), which sensitizes RY receptors, did not inhibit cAMP-PDEs, but it stimulated secretion in a glucose-dependent manner. The stimulation of secretion by caffeine and MBED involved both the first and the second phases of secretion. We conclude that the RY receptors of beta-cells mediate a distinct glucose-dependent signal for insulin secretion and may be a target for developing drugs that will stimulate insulin secretion only in a glucose-dependent manner.
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| 12. |
- Bruton, M, et al.
(author)
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Expression of High Mobility Group Protein B1 in Cardiac Tissue of Elderly Patients with Coronary Artery Disease with or without Inflammatory Rheumatic Disease
- 2017
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In: Gerontology. - : S. Karger AG. - 1423-0003 .- 0304-324X. ; 63:4, s. 337-349
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> It is known from clinical practice and observational studies that elderly patients with a diagnosis of inflammatory rheumatic diseases (IRD) bear a significantly increased risk for cardiovascular diseases such as coronary artery disease (CAD) and heart failure. The molecular mechanism, however, is still not known. Recently, high mobility group protein B1 (HMGB1), a ubiquitous, highly conserved single polypeptide expressed in all mammal eukaryotic cells, has been identified to mediate myocardial dysfunction in vitro once released from the nuclei of cardiomyocytes. <b><i>Objective:</i></b> To investigate whether HMGB1 and its receptors are expressed in cardiac muscles of elderly patients with CAD with or without IRD. <b><i>Methods:</i></b> HMGB1 and its 3 well-known receptors, receptor for advanced glycation end products, Toll-like receptor 2 (TLR2), and TLR4, were examined by immunohistochemistry on myocardial biopsy specimens from 18 elderly patients with CAD (10 with IRD, 8 without IRD). Furthermore, total HMGB1 protein levels were measured by Western blot from the cardiac biopsies in 5 patients with and 5 without IRD. <b><i>Results:</i></b> Pathologic cytosolic HMGB1 in cardiomyocytes was massively recorded in all patients with IRD, but only slightly expressed in 1 patient without IRD. Total HMGB1 levels were also consistently lower in myocardial muscle biopsies of patients with IRD compared to those without IRD. Furthermore, all 3 HMGB1 receptors were expressed in cardiomyocytes of all patients. <b><i>Conclusion:</i></b> The increased cytosolic expression of HMGB1 in cardiomyocytes and the lower total amount of HMGB1 in the cardiac specimens of IRD patients is consistent with a greater release of HMGB1 from the myocardial nuclei in IRD than non-IRD individuals. Thus, the HMGB1 signaling pathways may be more easily activated in elderly CAD patients with concomitant IRD and trigger a detrimental inflammatory process causing severe cardiovascular problems. Therefore, targeting HMGB1 in IRD patients might reduce the risk for cardiovascular events.
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| 13. |
- Bruton, Sean, et al.
(author)
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The Impact of Cosmic Variance on Inferences of Global Neutral Fraction Derived from Lyα Luminosity Functions during Reionization
- 2023
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 953:1
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Journal article (peer-reviewed)abstract
- We investigate the impact of field-to -field variation, deriving from cosmic variance, in measured Ly alpha emitter (LAE) luminosity functions (LFs) and this variation's impact on inferences of the neutral fraction of the intergalactic medium (IGM) during reionization. We post-process a z = 7 IGM simulation to populate the dark matter halos with LAEs. These LAEs have realistic UV magnitudes, Ly alpha fluxes, and Ly alpha line profiles. We calculate the attenuation of Ly alpha emission in universes with varying IGM neutral fraction, (x) over bar (H I). In a (x) over bar (H I) = 0.3 simulation, we perform 100 realizations of a mock 2 deg(2) survey with a redshift window Delta z = 0.5 and flux limit f(Ly alpha) > 1 x 10(-17)erg s(-1) cm(-2); such a survey is typical in depth and volume of the largest LAE surveys conducted today. For each realization, we compute the LAE LF and use it to recover the input x(H I). Comparing the inferred values of (x) over bar (H) (I) across the ensemble of the surveys, we find that cosmic variance, deriving from large-scale structure and variation in the neutral gas along the sightline, imposes a floor in the uncertainty of Delta(x) over bar (HI) similar to 0.2 when (x) over bar (H) (I) = 0.3. We explore mitigation strategies to decrease this uncertainty, such as increasing the volume, decreasing the flux limit, or probing the volume with many independent fields. Increasing the area and/or depth of the survey does not mitigate the uncertainty, but composing a survey with many independent fields is effective. This finding highlights the best strategy for LAE surveys aiming at constraining the (x) over bar (HI) of the universe during reionization.
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| 14. |
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| 15. |
- Gineste, Charlotte, et al.
(author)
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Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control
- 2022
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In: iScience. - : Elsevier. - 2589-0042. ; 25:12
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Journal article (peer-reviewed)abstract
- Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. By comparing adult mouse skeletal muscle fibers, isolated either by mechanical dissection or by collagenase-induced ECM digestion, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca2+ handling. RNA-sequencing showed striking differences in gene expression patterns between the two isolation methods with enzymatically dissociated fibers resembling myopathic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria following enzymatic dissociation. Repeated contractions resulted in a prolonged mitochondrial Ca2+ accumulation in enzymatically dissociated fibers, which was partially prevented by cyclophilin inhibitors. Of importance, muscle fibers of mice with severe mitochondrial myopathy show pathognomonic mitochondrial Ca2+ accumulation during repeated contractions and this accumulation was concealed with enzymatic dissociation, making this an ambiguous method in studies of native intracellular Ca2+ fluxes.
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| 23. |
- Piel, Sarah, et al.
(author)
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Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest
- 2024
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In: Scientific Reports. - 2045-2322. ; 14:1
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Journal article (peer-reviewed)abstract
- Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF’s protective mechanisms and optimize its therapeutic application in post-arrest care.
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| 24. |
- Stein, Martin, 1976-
(author)
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Evolution and taxonomy of Cambrian arthropods from Greenland and Sweden
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Arthropods have a rich fossil record spanning the Phanerozoic. Biomineralized forms such as the extinct trilobites are particularly common and are proven index fossils for biostratigraphy. Forms with an unmineralized cuticle are more rare, preserved only in so called konservat lagerstätten. Cambrian strata of Greenland have yielded rich trilobite faunas with potential for intercontinental correlation of Cambrian strata, but also an exceptionally preserved fauna, the Sirius Passet Lagerstätte. The first part of this thesis is concerned with trilobite biotratigraphy of the provisional Cambrian Series 2 in Greenland. The second part is concerned with exceptionally preserved arthropods from the Sirius Passet Lagerstätte, but also from 'Orsten' deposits from the Cambrian of Sweden. Perissopyge phenax occurs in the Henson Gletscher and Paralleldal formations spanning the Series 2 and 3 boundary interval in North Greenland. It also occurs in the Sekwi Formation of Yukon Territory, demonstrating that the species may hold potential for correlation within Laurentia. An indeterminate species of Perissopyge is shown to occur in the Ella Island Formation of North-East Greenland together with Olenellus cf. hanseni, which is similar to Olenellus cf. truemani described from the Henson Gletscher Formation. If this correlation is further corroborated it would offer a first tie-point for the An t'Sron Formation of North-West Scotland which yields Fritzolenellus lapworthi, herein reported for the first time from the Bastion Formation which underlies the Ella Island Formation. Oelandocaris oelandica from ‘Orsten’ deposits in the Cambrian series 3 and 4 boundary interval in Sweden is an early representative of the Crustacean stem lineage. Kiisortoqia avannaarsuensis is a new arthropod from the Sirius Passet Lagerstätte with robust antennulae strikingly similar to the 'raptorial' limb of the problematic anomalocaridids. The ventral morphology of the 'bivalved' Isoxys volucris is described for the first time and compared with other species assigned to Isoxys from Cambrian lagerstätten around the world. Finally, Siriocaris trolla, is a new arthropod that similarities with trilobites and certain ‘trilobitomorphs’ but seems to lack important synapomorphies of these taxa, though this may be due to preservational limitations in the material at hand.
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