| 1. |
- Jönsson, Karin, et al.
(författare)
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Evaluation of the degradation of desamino1,D-arginine8-vasopressin by nasal mucosa.
- 1992
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Ingår i: Acta Endocrinologica. - : Oxford University Press (OUP). - 0001-5598 .- 0804-4643 .- 1479-683X. ; 127:1, s. 27-32
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Tidskriftsartikel (refereegranskat)abstract
- The nasal route is a convenient and simple way to administer peptides to humans. Absorption of the drug, however, requires passage of the substance through the nasal mucosa. This is a possible site of enzymatic degradation of the peptide. It is shown that rabbit nasal mucosa homogenates rapidly degrade the synthetic anti-diuretic hormone analogue desamino1,D-arginine8-vasopressin in vitro. The metabolite formed has been identified as des-(amino,arginine8,glycineamide9)-vasopressin, which is stable under the prevalent in vitro incubation conditions. It is proposed that this process is catalyzed by intracellular post-proline cleavage enzyme. Reversed phase chromatography in combination with immunological detection has been used to study the possible presence of this metabolite in the circulation after intranasal administration to humans. The metabolite des-(amino,arginine8,glycineamide9)-vasopressin could not be detected in plasma following intranasal administration, possibly indicating a paracellular absorption of desamino1,D-arginine8-vasopressin or absence of this enzymatic activity in humans.
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| 2. |
- Serenius, Fredrik, et al.
(författare)
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Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden
- 2016
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Ingår i: Jama Pediatrics. - Chicago : American Medical Association (AMA). - 2168-6203 .- 2168-6211. ; 170:10, s. 954-963
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Active perinatal care increases the rate of survival of extremely preterm infants, but there are concerns that improved survival might increase the rate of disabled survivors. OBJECTIVE To determine the neurodevelopmental outcomes of a national cohort of children 6.5 years of age who had been born extremely preterm (<27 weeks' gestational age) in Sweden. DESIGN, SETTING, AND PARTICIPANTS Population-based prospective cohort study of consecutively born extremely preterm infants. All of these infants were born in Sweden during the period from April 1, 2004, to March 31, 2007. Of 707 live-born extremely preterm infants, 486 (68.7%) survived to 6.5 years of age. These children were assessed and compared with matched controls who had been born at term. Comparison estimates were adjusted for demographic differences. Assessments ended in February 2014, and analysis started thereafter. MAIN OUTCOMES AND MEASURES Cognitive ability was measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV), and the mean (SD) scores of the children who had been born extremely preterm were compared with those of the controls. Clinical examinations and parental questionnaires were used for diagnosis of cerebral palsy, hearing and vision impairments, and cognition for the children who were not assessed with the WISC-IV. RESULTS Of 486 eligible infants who were born extremely preterm, 441 (90.7%) were assessed at 6.5 years of age (59 by medical record review only) alongside 371 controls. The adjusted mean (SD) full-scale WISC-IV score was 14.2 (95% CI, 12.1-16.3) points lower for children who had been born extremely preterm than for controls. Cognitive disability was moderate for 18.8% of extremely preterm children and 2.2% of controls (P < .001), and it was severe for 11.1% of extremely preterm children and 0.3% of controls (P < .001). Cerebral palsy was observed in 9.5% of extremely preterm children and 0.0% of controls (P < .001), blindness was observed in 2.0% of extremely preterm children and 0.0% of controls (P < .001), and hearing impairment was observed in 2.1% of extremely preterm children and 0.5% of controls (P = .07). Overall, 36.1%(95% CI, 31.7%-40.6%) of extremely preterm children had no disability, 30.4%(95% CI 26.3%-34.8%) had mild disability, 20.2%(95% CI, 16.6%-24.2%) had moderate disability, and 13.4%(95% CI, 10.5%-16.9%) had severe disability. For extremely preterm children, moderate or severe overall disability decreased with gestational age at birth (adjusted odds ratio per week, 0.65 [95% CI, 0.54-0.79]; P < .001) and increased from 26.6% to 33.5%(P = .01) for children assessed both at 2.5 and 6.5 years. CONCLUSIONS AND RELEVANCE Of the 441 extremely preterm infants who had received active perinatal care, 293 (66.4%) had no or mild disability at 6.5 years; of the 371 controls, 11 (3.0%) had moderate or severe disability. Disability rates at 6.5 years increased relative to the rates at 2.5 years. Results are relevant for health care professionals and planners, and for clinicians counseling families facing extremely preterm births.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Brorson, Håkan, et al.
(författare)
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Breast Cancer-Related Chronic Arm Lymphedema Is Associated with Excess Adipose and Muscle Tissue.
- 2009
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Ingår i: Lymphatic Research and Biology. - : Mary Ann Liebert Inc. - 1539-6851 .- 1557-8585.
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: Arm lymphedema is a common complication after breast cancer treatment. Although conservative treatment can be used to reduce swelling, treatment often fails, possibly due to chronic edema being transformed from lymph fluid to subcutaneous fat, a condition called nonpitting lymphedema. It is currently unknown if the excess volume is solely due to excess in fat. This study evaluated whether dual energy X-ray absorptiometry (DXA) could be used to estimate the excess fat, muscle, and bone tissue in patients with arm lymphedema. Methods and Results: Eighteen women with arm lymphedema were investigated. Measurements were converted to volume values and compared with values obtained using plethysmography (PG). Linear regression equations and correlation equations were used to compare the DXA and the PG techniques in regard to total volume and excess volume in the lymphedematous arm. DXA was used to estimate excess fat, muscle, and bone volume in the lymphedematous arm. Both DXA and PG provided similar total arm volume and excess volume measurements for the lymphedematous arm. The lymphedematous arm showed 73% more fat, 47% more muscle, and 7% more bone by volume in the lymphedematous arm. Conclusions: Both excess fat and muscle volume contributed to the total excess volume in nonpitting arm lymphedema; excess soft tissue developed the first few years after breast cancer surgery. DXA can be used to identify patients with excess fat in their arms and thus unsuitable for conservative treatment and may be useful in estimating the amount of fat to remove in patients scheduled for liposuction.
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| 8. |
- Brorson, Håkan, et al.
(författare)
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Role of Compression after Liposuction
- 2016
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Ingår i: Veins and Lymphatics. - : PAGEPress Publications. - 2279-7483. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Liposuction, which is a very effective treatment modality to reduce lymphedema, can be performed as soon as the pitting component had been corrected by a phase of initial compression (Figure 1). Just like after conservative treatment, the use of compression garments after liposuction is very important to maintain the outcome.Garments should be prescribed in such numbers so that the edema does not recur. A common mistake is that the patient receive one, or if lucky two, garments, after treatment. When the arm or leg is swollen again the patient comes back to the therapist and treatment starts again, and so on. Instead the patient must be followed up at his needs in order to prevent recurrence. This means that treatment must be individualized. An elderly woman may need two garments every 6 months, while a young active patient with a heavy work may need two garments every month. One can draw a parallel to the dosage of insulin to a patient with diabetes that in the same way must be individualized. Nobody prescribes two vials of insulin for 6 months, when the patient needs that same amount for one month.The purpose of compression therapy is to increase the interstitial pressure so that the capillary filtration is decreased. When treated with standard compression garments a study showed a reduction of the excess volume (1680 mL; range 670-3320) after two weeks with 20% (range 5-37) corresponding to 338 ml (range 95-1225).1 Studies of treatment for 6 months have shown a reduction of excess volume of 17% (range 16-52), corresponding to a volume of 139 mL (range 150-345).2Compression garments can be used at the onset of symptoms to possibly prevent the development of lymphedema. Garments that are used throughout the day (15 years’ follow-up)3 as well as only daytime (6 months follow-up)2 prevent the edema to recur.Compression garments must be ordered by a qualified and experienced lymphedema team, consisting of a lymph therapist with a basic education in physiotherapy or occupational therapy and a physician. The team should have vast knowledge regarding various compression trademarks and how to take measurements for ordering of garments. In order to increase compliance and feedback, the team should never let the patient have the measurements for ordering of garments taken by a retailer outside of the team.
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| 9. |
- Brorson, Håkan, et al.
(författare)
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Suction-assisted lipectomy
- 2015
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Ingår i: Lymphedema : Presentation, Diagnosis, and Treatment - Presentation, Diagnosis, and Treatment. - Cham : Springer International Publishing. - 9783319144924 - 9783319144931 ; , s. 313-324
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Bokkapitel (refereegranskat)abstract
- 39.Brorson H, Svensson B, Ohlin K. Suction-Assisted Lipectomy. In: Greene AK, Slavin S, Brorson H, editors, Lymphedema - Presentation, Diagnosis, and Treatment. Cham, Switzerland: Springer; 2015: p. 313-324.
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| 10. |
- Brorson, Håkan, et al.
(författare)
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Volume measurements and follow-up
- 2015
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Ingår i: Lymphedema : Presentation, Diagnosis, and Treatment - Presentation, Diagnosis, and Treatment. - Cham : Springer International Publishing. - 9783319144924 - 9783319144931 ; , s. 115-122
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Bokkapitel (refereegranskat)
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| 11. |
- Hoffner, Mattias, et al.
(författare)
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Liposuction Gives Complete Reduction of Arm Lymphedema following Breast Cancer Treatment : A 5-year Prospective Study in 105 Patients without Recurrence
- 2018
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Ingår i: Plastic and reconstructive surgery (1963). - : LIPPINCOTT WILLIAMS & WILKINS. - 0032-1052 .- 1529-4242. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Arm lymphedema is a well-recognized complication after breast cancer surgery that negatively impacts patients' quality of life, both physiologically and psychologically. Lymph stasis and inflammation result in excess formation of adipose tissue, which makes removal of the deposited subcutaneous fat necessary to eliminate the excess volume. Liposuction, combined with postoperative controlled compression therapy (CCT), is the only treatment that gives complete reduction of the excess volume. The aim of this study was to evaluate the 5-year results after liposuction in combination with CCT. Methods: Patients consecutively operated on between 1993 and 2012 were identified from the lymphedema registry, comprising all patients with nonpitting lymphedema treated with liposuction and CCT in our department. Standardized forms were used to collect pre-, peri-, and postoperative data. Results: One hundred five women with nonpitting edema were treated. The mean interval between the breast cancer operation and lymphedema start was 2.95.0 years, the mean duration of lymphedema was 10 +/- 7.4 years, and the preoperative mean excess volume was 1,573 +/- 645ml. The mean volume aspirated was 1,831 +/- 599ml. Postoperative mean reduction 5 years postoperatively was 117% +/- 26% as compared with the healthy arm. Conclusion: Liposuction is an effective method for the treatment of chronic, nonpitting, arm lymphedema resistant to conservative treatment. The volume reduction remains complete after 5 years.
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| 12. |
- Hueting, David A., et al.
(författare)
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Design, structure and plasma binding of ancestral β-CoV scaffold antigens
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interact with plasma of patients recovered from COVID-19 but do not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yield high resolution structures (2.6–2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. The structures reveal an intricate hydrogen-bonding network mediated by well-resolved loops, both within and across monomers, tethering the N-terminal domain and RBD together. We show that AnSA-5 can induce and boost a broad-spectrum immune response against the wild-type RBD as well as circulating variants of concern in an immune organoid model derived from tonsils. Finally, we highlight how AnSAs are potent scaffolds by replacing the ancestral RBD with the wild-type sequence, which restores ACE2 binding and increases the interaction with convalescent plasma.
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| 13. |
- Karlsson, Tobias, et al.
(författare)
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Complete Reduction of Leg Lymphedema after Liposuction : A 5-Year Prospective Study in 67 Patients without Recurrence
- 2023
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Ingår i: Plastic and Reconstructive Surgery - Global Open. - 2169-7574. ; 11:12, s. 5429-5429
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lymphedema leads to adipose tissue deposition that cannot be removed using conservative methods. Previous studies have shown a complete reduction in excess volume in limbs with lymphedema when treated with liposuction and controlled compression therapy (CCT). We present the long-term outcomes of all patients treated with liposuction and CCT for lower extremity lymphedema (LEL) who were followed up for 5 years. Methods: Sixty-seven LEL patients underwent liposuction and CCT. Thirty-six patients had primary lymphedema and 31 patients had secondary lymphedema. The outcomes included excess leg volume over a follow-up period of 5 years. Any association between patient characteristics and treatment outcomes was analyzed. Results: The preoperative excess volume prior was 3515 mL [interquartile range (IQR): 2225-5455 mL], and the volume ratio to the unaffected leg was 1.35 (IQR: 1.25-1.53). One year after treatment, the excess volume decreased by 101% (IQR: 84-116). The decrease in excess volume continued during the 5-year follow-up, and at the end of the study, the excess volume had decreased by 115% (IQR: 98-124). No major complications were noted. Conclusions: Liposuction and CCT are safe and effective procedures for removing excess adipose tissue and normalizing the leg volume in patients with late-stage LEL. When no satisfactory results are obtained with conservative methods, such as complex decongestive therapy, and there is no or minimal pitting on limb examination, excess adipose tissue is present, and liposuction can be considered.
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| 14. |
- Karlsson, Tobias, et al.
(författare)
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Liposuction of Breast Cancer: Related Arm Lymphedema Reduces Fat and Muscle Hypertrophy
- 2022
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Ingår i: Lymphatic Research and Biology. - : Mary Ann Liebert Inc. - 1539-6851 .- 1557-8585. ; 20:1, s. 53-63
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Adipose tissue deposition is a known consequence of lymphedema. A previous study showed that the affected arm in patients with nonpitting breast cancer-related lymphedema (BCRL) had a mean excess volume of 73% fat and 47% muscle. This condition impairs combined physiotherapy as well as more advanced microsurgical methods. Liposuction is, therefore, a way of improving the effects of treatment. Objective: This study aims to evaluate the tissue changes in lymphedematous arms after liposuction and controlled compression therapy (CCT) in patients with nonpitting BCRL. Methods and Results: Eighteen women with an age of 61 years and a duration of arm lymphedema (BCRL) of 9 years were treated with liposuction and CCT. Tissue composition of fat, lean (muscle), and bone mineral was analyzed through dual energy X-ray absorptiometry (DXA) before, and at 3 and 12 months after surgery. Excess volumes were also measured with plethysmography. The median DXA preoperative excess volume was 1425 mL (704 mL fat volume, 651 mL lean volume). The DXA excess volume at 3 months after surgery was 193 mL (-196 mL fat volume, 362 mL lean volume). At 12 months after surgery, the median excess DXA volume was 2 mL (-269 mL fat volume, 338 mL lean volume). From before surgery to 3 months after surgery, the median DXA excess volume reduced by 85% (p < 0.001) (fat volume reduction 128% (p < 0.001), lean volume reduction 37% (p = 0.016)). From before surgery to 12 months after surgery, it reduced by 100% (p < 0.001) (fat volume reduction 139% [p < 0.001], lean volume reduction 54% [p = 0.0013]). Conclusions: Liposuction and CCT effectively remove the excess fat in patients with nonpitting BCRL, and a total reduction of excess arm volume is achievable. A postoperative decrease in excess muscle volume is also seen, probably due to the reduced weight of the arm postoperatively.
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| 15. |
- Lundin, Stefan, et al.
(författare)
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Pharmacokinetic and pharmacologic properties of antiuterotonic oxytocin analogs in the rat
- 1993
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 1521-0103. ; 264:2, s. 783-788
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacologic and pharmacokinetic properties were evaluated in a series of antiuterotonic oxytocin analogs, modified at positions 1, 2, 4, 8 and, in one case, position 9 of the oxytocin (OT) molecule. [Mpa1,D-Tyr2(Et),Val4,Orn8,desGly9]-OT, [Mpa1,Tyr2(Et),Val4,Orn8]-OT and [Mpa1,D-Tyr2,Val4,Orn8]-OT displayed similar plasma clearance rates (Clps) using the constant infusion method in rats. Two analogs, [Mpa1,D-Tyr2(Et),Val4,Orn8]-OT and, particularly, [Mpa1,D-Tyr2(Et),Thr4,Orn8]-OT, were cleared at significantly higher rates compared with the others. [Mpa1, D-Tyr2(Et), Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT were most potent in eliciting a short-term in vivo antiuterotonic effect, whereas the duration of effect was longest for [Mpa1, D-Tyr2, Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT. The Clp of [Mpa1, D-Tyr2, Val4, Orn8]-OT was similar regardless of the infusion rate. No relationship between antiuterotonic effect and Clp of the five peptides could be demonstrated, and no significant linear correlation between Clp and effect duration was found. The apparent volumes of distribution for the present analogs were 10-fold larger than the blood volume, a finding to be considered when measuring in vivo antagonistic activity. The 24-h urinary excretion ranged from 14.3 to 25.6% of the i.v. dose and was negatively correlated with peptide lipophilicity. It is concluded that, in addition to diverging pharmacologic properties, peptide analogs may differ markedly in kinetic parameters like Clp, volumes of distribution and urinary excretion despite minor molecular modifications.
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| 16. |
- Ohlin, Andreas, 1972-, et al.
(författare)
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Sepsis as a risk factor for neonatal morbidity in extremely preterm infants
- 2015
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell. - 0803-5253 .- 1651-2227. ; 104:11, s. 1070-1076
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This study evaluated sepsis as a risk factor for neonatal morbidities and investigated the association between specific pathogens and neonatal morbidities.Methods: This was a nationwide Swedish prospective cohort study, consisting of the 497 extremely premature children, who were born before 27weeks of gestation between 2004 and 2007 and survived their first year of life. Neonatal sepsis was evaluated as a risk factor for neonatal morbidity using multiple logistic linear regression analyses.Results: We found that 326 (66%) of the infants had at least one sepsis episode and coagulase-negative staphylococci was the most common pathogen. Definite sepsis, with an odds ratio (OR) of 1.6, was associated with severe bronchopulmonary dysplasia, but not clinical sepsis (OR 1.1). Definite sepsis was also associated with a prolonged hospital stay (OR 1.6). Sepsis was not significantly associated with a higher risk of retinopathy of prematurity or intraventricular haemorrhage.Conclusion: Extremely preterm infants face a great risk of acquiring neonatal sepsis, with coagulase-negative staphylococci being the most common pathogen in this population. Definite sepsis seemed to be a risk factor for severe bronchopulmonary dysplasia and prolonged hospital stay, but the associations were weaker than in previous studies.
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| 17. |
- Ohlin, Karin, et al.
(författare)
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Controlled compression therapy and compression garments
- 2015
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Ingår i: Lymphedema : Presentation, Diagnosis, and Treatment - Presentation, Diagnosis, and Treatment. - Cham : Springer International Publishing. - 9783319144924 - 9783319144931 ; , s. 213-225
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Bokkapitel (refereegranskat)
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| 18. |
- Pauly, Frida, et al.
(författare)
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Protein Expression Profiling of Formalin-Fixed Paraffin-Embedded Tissue Using Recombinant Antibody Microarrays
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:12, s. 5943-5953
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Tidskriftsartikel (refereegranskat)abstract
- Proteomics, the large-scale analysis of proteins, is a rapidly evolving field with an increasing number of key clinical applications, such as diagnosis, prognosis, and classification. In order to generate complete protein expression profiles, or protein atlases, any crude sample format must be addressable in a rapid, multiplex, and sensitive manner. A common and clinically central sample format, formalin-fixed, paraffin-embedded (FFPE) tissue material, holds great potential as a source for disease-associated biomarker signatures. However, despite major efforts, extraction and subsequent profiling of proteins from FFPE tissue has proven to be challenging. In this proof-of-concept study, we have demonstrated for the first time that proteins could be extracted, labeled, and subsequently profiled in a multiplex, sensitive, and reproducible manner using recombinant scFv antibody microarrays. Thus, we have added FFPE samples to the list of sample formats available for high-throughput analysis by affinity proteomics, paving the way for the next generation of biomarker-driven discovery projects.
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| 19. |
- Persson, Jonas, et al.
(författare)
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Molecular evolution of specific human antibody against MUC1 mucin results in improved recognition of the antigen on tumor cells.
- 2009
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Ingår i: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 30:4, s. 221-31
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Tidskriftsartikel (refereegranskat)abstract
- The MUC1 mucin is differentially expressed and glycosylated in cancer tissue as opposed to healthy tissue. Due to these differences, MUC1 is considered a potential biomarker suitable for cancer diagnosis and therapy. In a previous study, the human MUC1-specific antibody 12ESC-6 was able to bind a sequence variant of the tandem repeat of MUC1 that is not recognized by many other MUC1-specific antibodies. It was also found to bind efficiently to MUC1-carrying cells. We have now used 12ESC-6 as starting point for random mutagenesis to isolate variants with improved ability to bind MUC1 in human tumor tissue. The resulting 12ESC-6 variants were shown to recognize not only the naked MUC1 tandem repeat but even more so glycosylated variants thereof, in particular those carrying the GalNAc (Tn) glycoform. Selected variants of 12ESC-6 demonstrated improved staining of MUC1 on cell lines using flow cytometry and improved staining of the antigen in breast tumor tissue by immunohistochemistry. Molecular evolution and specific fine-tuning thus have the potential to improve the performance of antibody specificities targeting tumor-associated epitopes on MUC1 mucin.
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| 20. |
- Pettersson, Miriam, 1977-, et al.
(författare)
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Home phototherapy for hyperbilirubinemia in neonates : an unblinded multicentre randomised controlled trial
- 2023
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Ingår i: Örebro University's Nobel Day Festivities. - 9789187789922
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Konferensbidrag (refereegranskat)abstract
- Background/Objective: The aim of this study was to assess whether home phototherapy is a safe alternative to hospital treatment.Method: This was a randomised controlled, multicentre, trial in which term newborns with a total serum bilirubin of 300-400 μmol/ were randomized to either home phototherapy or conventional in-hospital phototherapy.The outcome measurements were parent-infant bonding, stress and measurements of safety and feasibility. A descriptive qualitative study based on interviews was performed as well as a health economic analysis.Result: 147 patients were recruited from 6 hospitals, Results showed no difference between groups in the safety and feasibility outcomes. Parents in the intervention group had better scores on bonding and lower levels of stress. The interviews showed that parents felt secure at home. The cost per patient was €337 for home phototherapy compared with €1156 for the hospital alternative indicating average cost savings of €819 or 71% per patient.Conclusion: Home phototherapy can be considered a safe and feasible alternative to hospital care for well selected patients. It improves bonding and stress for parents and reduces health care costs. Since the first publication from this study was published home phototherapy is now recommended by the American Academy of Pediatrics as an alternative to hospital care for patients with uncomplicated hyperbilirubinemia.
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| 21. |
- Syrén, Per-Olof, et al.
(författare)
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Design, structure and plasma binding of ancestral β-CoV scaffold antigens
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The pandemic caused by Severe acute respiratory syndrome coronavirus 2 has had devastating consequences on global health and economy. Despite the success of vaccination campaigns emerging variants are of concern and novel viruses with the potential to drive future pandemics are circulating in nature. Development of vaccines can be challenging, as key viral protein antigens can be unstable or aggregate. In this study, we present the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interacted with plasma of patients recovered from COVID-19 but did not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yielded high resolution structures (2.6-2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. This captured closed state is stabilised by an intricate hydrogen‑bonding network mediated by well-resolved loops, both within and across monomers, tethering the N‑terminal domain and RBD together, which determines their relative spatial orientation. Finally, we show how AnSAs are potent scaffolds by replacing the ancestral RBD with the Wuhan wild-type sequence, which restored ACE2 binding and increased the interaction with convalescent plasma. In contrast to rational antigen design depending on prior structural knowledge, our work highlights how stable and potentially interesting antigens can be generated using exclusively available sequence information.
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| 22. |
- Tengrup, Ingrid, et al.
(författare)
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8 Uppföljning
- 2003
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Ingår i: Lymfödem. Nationellt vårdprogram.. - 9163145316 ; , s. 45-45
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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