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- Trkulja, C. L., et al.
(författare)
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Rational antibody design for undruggable targets using kinetically controlled biomolecular probes
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:16
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Lemma, M, et al.
(författare)
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Streptococcus pneumoniae Nasopharyngeal Carriage among PCV-10-Vaccinated HIV-1-Infected Children with Maintained Serological Memory in Ethiopia
- 2020
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Ingår i: Pathogens (Basel, Switzerland). - : MDPI AG. - 2076-0817. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae (S. pneumoniae) vaccines have substantially reduced the burden of invasive pneumococcal diseases (IPDs) worldwide. Despite high coverage with S. pneumoniae vaccination, upper-respiratory-tract colonization by S. pneumoniae is still common. We assessed maintenance of serological responses to S. pneumoniae serotypes included in PCV-10 by ELISA in HIV-1-infected children (n = 50) and age-matched controls (n = 50) in Ethiopia. We isolated S. pneumoniae in nasopharyngeal swabs and determined S. pneumoniae serotype by whole genome sequencing (WGS). Comparable levels of S. pneumoniae serotype-specific IgG concentrations were detected in plasma of HIV-1-infected children and matched controls, with geometric mean concentrations (GMCs) consistently higher than the protective threshold for PCV-10 serotypes of 0.35 μg/mL. We isolated S. pneumoniae from 38 (out of 97) nasopharyngeal swabs, 25 from HIV-1-infected children and 13 from controls. WGS based serotyping revealed 22 known S. pneumoniae serotypes and 2 nontypeable (NT) isolates. Non-PCV-10 serotypes represented >90% of isolates. We showed that HIV-1-infected children and matched controls in Ethiopia carry a level of maintained serological memory to PCV-10 considered protective for IPDs. We identified a higher proportion of nasopharyngeal carriage with highly pathogenic S. pneumoniae non-PCV strains among HIV-1-infected children compared to controls.
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| 5. |
- Lundblad, Matilda, 1982, et al.
(författare)
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Epidemiological Data on LCL and PCL Injuries Over 17 Seasons in Men's Professional Soccer: The UEFA Elite Club Injury Study
- 2020
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Ingår i: Open Access Journal of Sports Medicine. - 1179-1543. ; 11, s. 105-112
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is limited epidemiological information on injury rates and injury mechanisms for lateral collateral ligament (LCL) and posterior cruciate ligament (PCL) injuries in male professional soccer. In addition, time trends and lay-off times for these injuries have not yet been determined. Aim: To determine injury rates and circumstances of LCL and PCL injuries over 17 seasons in men's professional soccer. Methods: A prospective cohort study, in which 68 professional European soccer teams were followed over 17 consecutive seasons (2001/2002 to 2017/2018). The teams' medical staff recorded player exposure and time-loss injuries. Lay-off time was reported as the median and the first and third quartile. Injury rate was defined as the number of injuries per 1000 playerhours. Results: One hundred and twenty-eight LCL and 28 PCL injuries occurred during 2,554,686 h of exposure (rate 0.05 and 0.01/1000 h, respectively). The median lay-off time for LCL injuries was 15 (Q(1)=7, Q(3)=32) days, while it was 31 days for PCL injuries (Q(1)=15, Q(3)=74). The match injury rate for LCL injuries was 11 times higher than the training injury rate (0.21 vs 0.02/1000 h, rate ratio [RR] 10.5, 95% CI 7.3 to 15.1 p<0.001) and the match injury rate for PCL injuries was 20 times higher than the training injury rate (0.056 vs 0.003/1000 h, RR 20.1, 95% CI 8.2 to 49.6, p<0.001). LCL injuries saw a significant annual decrease of approximately 3.5% (p=0.006). In total, 58% (63/108) of all LCL injuries and 54% (14/26) of all PCL injuries were related to contact mechanism. Conclusion: This study with prospectively registered data on LCL and PCL injuries in men's professional soccer shows that the median lay-off from soccer for LCL and PCL injuries is approximately 2 and 4 weeks respectively. These rare knee ligament injuries typically occur during matches and are associated with a contact injury mechanism.
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