| 1. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 2. |
- CARLSSON, STEFAN, 1987, et al.
(författare)
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Age at surgery, educational level and long-term urinary incontinence after radical prostatectomy
- 2011
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 108:10, s. 1572-1577
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To identify predictors for long-term urinary leakage after radical prostatectomy. PATIENTS AND METHODS A consecutive series of 1411 patients who underwent radical prostatectomy (open surgery or robot-assisted laparoscopic surgery) at Karolinska University Hospital between 2002 and 2006 were invited to complete a study-specific questionnaire. Urinary leakage was defined as use of two or more pads per day. RESULTS Questionnaires were received from 1288 (91%) patients with a median follow-up of 2.2 years. Age at surgery predicts in an exponential manner long-term urinary incontinence at follow-up with an estimated relative increase of 6% per year. Among the oldest patients, 19% had urinary incontinence compared with 6% in the youngest age group, translating to a prevalence ratio of 2.4 (95% confidence interval [CI], 1.5-8.1). Low educational level, as compared with high, yielded an increased age-adjusted prevalence ratio of 2.5 (95% CI, 1.7-3.9). Patients who had undergone salvage radiation therapy had an increased prevalence of urinary incontinence (2.5; 95% CI, 1.6-3.8), as did those with respiratory disease (2.4; 95% CI, 1.3-4.4). Body mass index, prostate weight, presence of diabetes or previous transurethral resection did not appear to influence the prevalence of urinary incontinence. CONCLUSIONS In this series, a patient's age at radical prostatectomy influenced, in an exponential manner, his risk of long-term urinary incontinence. Other predictors are low educational level, salvage radiation therapy and respiratory disease. Intervention studies are needed to understand if these data are relevant to the prevalence of urinary leakage if a radical prostatectomy is postponed in an active monitoring programme.
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| 3. |
- CARLSSON, STEFAN, 1987, et al.
(författare)
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Orgasm-Associated Urinary Incontinence and Sexual Life after Radical Prostatectomy.
- 2011
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Ingår i: The journal of sexual medicine. - : Oxford University Press (OUP). - 1743-6109 .- 1743-6095.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Involuntary release of urine during sexual climax, orgasm-associated urinary incontinence, occurs frequently after radical prostatectomy. We know little about its prevalence and its effect on sexual satisfaction. Aim. To determine the prevalence of orgasm-associated incontinence after radical prostatectomy and its effect on sexual satisfaction. Methods. Consecutive series, follow-up at one point in calendar time of men having undergone radical prostatectomy (open surgery or robot-assisted laparoscopic surgery) at Karolinska University Hospital, Stockholm, Sweden, 2002-2006. Of the 1,411 eligible men, 1,288 (91%) men completed a study-specific questionnaire. Main Outcome Measure. Prevalence rate of orgasm-associated incontinence. Results. Of the 1,288 men providing information, 691 were sexually active. Altogether, 268 men reported orgasm-associated urinary incontinence, of whom 230 (86%) were otherwise continent. When comparing them with the 422 not reporting the symptom but being sexually active, we found a prevalence ratio (with 95% confidence interval) of 1.5 (1.2-1.8) for not being able to satisfy the partner, 2.1 (1.1-3.5) for avoiding sexual activity because of fear of failing, 1.5 (1.1-2.1) for low orgasmic satisfaction, and 1.4 (1.2-1.7) for having sexual intercourse infrequently. Prevalence ratios increase in prostate-cancer survivors with a higher frequency of orgasm-associated urinary incontinence. Conclusion. We found orgasm-associated urinary incontinence to occur among a fifth of prostate cancer survivors having undergone radical prostatectomy, most of whom are continent when not engaged in sexual activity. The symptom was associated with several aspects of sexual life. Nilsson AE, Carlsson S, Johansson E, Jonsson MN, Adding C, Nyberg T, Steineck G, and Wiklund NP. Orgasm-associated urinary incontinence and sexual life after radical prostatectomy. J Sex Med **;**:**-**.
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| 4. |
- Cortés-González, Jeff R, et al.
(författare)
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Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: Single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy.
- 2013
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Ingår i: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 42:1, s. 109-17
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the role of 70Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA >0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p<0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8-10 in the prostatectomy specimens 17/40(43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA >1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT) <10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3-4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in >50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Stranne, Johan, 1970, et al.
(författare)
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Inguinal Hernia After Radical Prostatectomy for Prostate Cancer : Results From a Randomized Setting and a Nonrandomized Setting
- 2010
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 58:5, s. 719-726
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Tidskriftsartikel (refereegranskat)abstract
- Background: Observational data indicate that retropubic radical prostatectomy (RRP) for prostate cancer (PCa) may induce inguinal hernia (IH) formation. Little is known about the influence of robot-assisted radical prostatectomy (RALP) on IH risk. Objective: To compare the incidence of IH after RRP and RALP to that of nonoperated patients with PCa and to a population control. Design, setting, and participants: We studied two groups. All 376 men included in the Scandinavian Prostate Cancer Group Study Number 4 constitute study group 1. Patients were randomly assigned RRP or watchful waiting (WW). The 1411 consecutive patients who underwent RRP or RALP at Karolinska University Hospital constitute study group 2. Men without PCa, matched for age and residence to each study group, constitute controls. Measurements: Postoperative IH incidence was detected through a validated questionnaire. The participation rates were 82.7% and 88.4% for study groups 1 and 2, respectively. Results and limitations: The Kaplan-Meier cumulative occurrence of IH development after 48 mo in study group 1 was 9.3%, 2.4%, and 0.9% for the RRP, the WW, and the control groups, respectively. There were statistically significant differences between the RRP group and the WW and control groups, but not between the last two. In study group 2 the cumulative risk of IH development at 48 mo was 12.2%, 5.8%, and 2.6% for the RRP, the RALP, and the control group, respectively. There were statistically significant differences between the RRP group and the RALP and control groups, but not between the last two. Conclusions: RRP for PCa leads to an increased risk of IH development. RALP may lower the risk as compared to open surgery.
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| 9. |
- Begnini, Fabio, et al.
(författare)
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Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction
- 2022
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:4, s. 3473-3517
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Tidskriftsartikel (refereegranskat)abstract
- Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands.
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| 10. |
- Begnini, Fabio, et al.
(författare)
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Structure-based optimization of a macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Activation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes a potential opportunity for the treatment of oxidative stress related disease. Although highly potent inhibitors of the Keap1–Nrf2 protein-protein interaction (PPI) have been reported, these compounds are based on a few reoccurring scaffolds. Here, we report a novel, structurally unique series of double-digit nM Keap1 inhibitors obtained by optimization of a natural product-derived macrocyclic lead. Exploration of the structure-activity relationship, followed by structure-based design led to a 100-fold improvement in inhibitory potency compared to the starting point. The macrocyclic core positions the pharmacophores of the inhibitors suitably for productive interactions with key residues of Keap1, including R415 and R483; both of which contribute to the highly polar nature of the binding site for Nrf2. In addition, we discovered that minor, ligand-induced reorganizations of these two arginine residues are accompanied by major differences in binding affinity between compounds in the series.
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| 11. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 12. |
- Carlsson, Sven A., et al.
(författare)
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Towards a Design Science Research Approach for IS Use and Management: : Applications from the Areas of Knowledge Management, E-learning and IS Integration
- 2008
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Ingår i: Proceedings of the Third International Conference on Design Science Research in Information Systems and Technology (DESRIST 2008). ; , s. 111-131
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Konferensbidrag (refereegranskat)abstract
- Design science research is an essential part of IS research since the field should not only try to understand how the world is but also how to change it. We argue that the aim of IS design science research should be to develop practical knowledge not only for the design and improvement of IS but also for IS use and management. Whereas substantial methodological support exists for researchers engaged in behavioral IS research, only limited methodological support exists for researchers with the ambition to develop new IS design theories and new IT artifacts. For the development of design theories for IS use and management the methodological support is even weaker. To overcome this shortcoming we suggest an approach for design research on IS use and management. We give three examples of the proposed approach in use by applying it to the areas of knowledge management systems, e-learning and IS integration.
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| 13. |
- Carlsson, Sven, et al.
(författare)
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An Approach for Designing Management Support Systems: The Design Science Research Process and its Outcomes
- 2009
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Konferensbidrag (refereegranskat)abstract
- Design science research involves creating and evaluating innovative methods and approaches to be used in design practice. We present an approach to be used in the process of designing Management Support Systems (MSS). The nature of managerial work makes the design, development, and implementation of MSS a major challenge. The MSS literature suggests that determining MSS requirements and specification of MSS are the most critical phases in MSS design and development. We present an approach that can be used as a guide for MSS design, with a primary focus on MSS requirements determination and how requirements can be fulfilled using information and communication technologies (ICT). The approach builds on Quinn and associates’ competing values model (CVM) of organizational effectiveness. The approach can guide MSS designers in designing MSS that support different managerial roles, i.e., the development of MSS that support managerial cognition, decision, and action.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Corsini, Christian, et al.
(författare)
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Patient-reported side effects 1 year after radical prostatectomy or radiotherapy for prostate cancer : a register-based nationwide study
- 2024
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Ingår i: European Urology Oncology. - : Elsevier. - 2588-9311. ; 7:3, s. 605-613
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Data on functional and psychological side effects following curative treatment for prostate cancer are lacking from large, contemporary, unselected, population-based cohorts.OBJECTIVE: To assess urinary symptoms, bowel disturbances, erectile dysfunction (ED), and quality of life (QoL) 12 mo after robot-assisted radical prostatectomy (RARP) and radiotherapy (RT) using patient-reported outcome measures in the Swedish prostate cancer database.DESIGN, SETTING, AND PARTICIPANTS: This was a nationwide, population-based, cohort study in Sweden of men who underwent primary RARP or RT between January 1, 2018 and December 31, 2020.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Absolute proportions and odds ratios (ORs) were calculated using multivariable logistic regression, with adjustment for clinical characteristics.RESULTS AND LIMITATIONS: A total of 2557 men underwent RARP and 1741 received RT. Men who underwent RT were older (69 vs 65 yr) and had more comorbidities at baseline. After RARP, 13% of men experienced incontinence, compared to 6% after RT. The frequency of urinary bother was similar, at 18% after RARP and 18% after RT. Urgency to defecate was reported by 14% of men after RARP and 34% after RT. At 1 yr, 73% of men had ED after RARP, and 77% after RT. High QoL was reported by 85% of men after RARP and 78% of men after RT. On multivariable regression analysis, RT was associated with lower risks of urinary incontinence (OR 0.25, 95% confidence interval [CI] 0.19-0.33), urinary bother (OR 0.79, 95% CI 0.66-0.95), and ED (OR 0.54, 95% CI 0.46-0.65), but higher risk of bowel symptoms (OR 2.86, 95% CI 2.42-3.39). QoL was higher after RARP than after RT (OR 1.34, 95% CI 1.12-1.61).CONCLUSIONS: Short-term specific side effects after curative treatment for prostate cancer significantly differed between RARP and RT in this large and unselected cohort. Nevertheless, the risk of urinary bother was lower after RT, while higher QoL was common after RARP.PATIENT SUMMARY: In our study of patients treated for prostate cancer, urinary bother and overall quality of life are comparable at 1 year after surgical removal of the prostate in comparison to radiotherapy, despite substantial differences in other side effects.
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| 18. |
- Corsini, Christian, et al.
(författare)
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Patient-reported Side Effects 1 Year After Radical Prostatectomy or Radiotherapy for Prostate Cancer : A Register-based Nationwide Study
- 2024
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Ingår i: European Urology Oncology. - : Elsevier. - 2588-9311. ; 7:3, s. 605-613
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data on functional and psychological side effects following curative treatment for prostate cancer are lacking from large, contemporary, unselected, populationbased cohorts. Objective: To assess urinary symptoms, bowel disturbances, erectile dysfunction (ED), and quality of life (QoL) 12 mo after robot -assisted radical prostatectomy (RARP) and radiotherapy (RT) using patient -reported outcome measures in the Swedish prostate cancer database. Design, setting, and participants: This was a nationwide, population -based, cohort study in Sweden of men who underwent primary RARP or RT between January 1, 2018 and December 31, 2020. Outcome measurements and statistical analysis: Absolute proportions and odds ratios (ORs) were calculated using multivariable logistic regression, with adjustment for clinical characteristics. Results and limitations: A total of 2557 men underwent RARP and 1741 received RT. Men who underwent RT were older (69 vs 65 yr) and had more comorbidities at baseline. After RARP, 13% of men experienced incontinence, compared to 6% after RT. The frequency of urinary bother was similar, at 18% after RARP and 18% after RT. Urgency to defecate was reported by 14% of men after RARP and 34% after RT. At 1 yr, 73% of men had ED after RARP, and 77% after RT. High QoL was reported by 85% of men after RARP and 78% of men after RT. On multivariable regression analysis, RT was associated with lower risks of urinary incontinence (OR 0.25, 95% confidence interval [CI] 0.19- 0.33), urinary bother (OR 0.79, 95% CI 0.66-0.95), and ED (OR 0.54, 95% CI 0.46-0.65), but higher risk of bowel symptoms (OR 2.86, 95% CI 2.42-3.39). QoL was higher after RARP than after RT (OR 1.34, 95% CI 1.12-1.61). Conclusions: Short-term specific side effects after curative treatment for prostate cancer significantly differed between RARP and RT in this large and unselected cohort. Nevertheless, the risk of urinary bother was lower after RT, while higher QoL was common after RARP. Patient summary: In our study of patients treated for prostate cancer, urinary bother and overall quality of life are comparable at 1 year after surgical removal of the prostate in comparison to radiotherapy, despite substantial differences in other side effects. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 19. |
- Henningsson, Stefan, et al.
(författare)
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Socio-technical IS design science research : developing design theory for IS integration management
- 2011
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Ingår i: Information Systems and E-Business Management. - : Springer Science and Business Media LLC. - 1617-9846 .- 1617-9854. ; 9:1, s. 109-131
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Tidskriftsartikel (refereegranskat)abstract
- Design science research is an essential part of IS research since the field should not only try to understand how the world is, but also how to change it. We argue that the aim of IS design science research should be to develop practical knowledge not only for the design of novel information technology (IT), but also for IS governance and management. Whereas at least some methodological support exists for researchers engaged in IT-centric design science research, limited support is available for researchers who want to develop design knowledge and theory for IS governance and management. To overcome this shortcoming, we suggest a socio-technical IS design science research approach. The approach has four main activities: (1) identifying problem situations and desired outcomes, (2) reviewing extant theories, knowledge and data, (3) proposing/refining design theory and knowledge, and (4) testing design theory and knowledge. The applicability and usefulness of the proposed approach is shown by means of a design science research project concerning IS integration management in the context of mergers and acquisitions.
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| 20. |
- King, Carina, et al.
(författare)
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COVID-19—a very visible pandemic
- 2020
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 396:10248, s. 15-15
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Tidskriftsartikel (refereegranskat)
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| 21. |
- Lundberg, Stefan, et al.
(författare)
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Nicotine treatment of obsessive-compulsive disorder
- 2004
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Ingår i: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY. - : Elsevier BV. - 0278-5846. ; 28:7, s. 1195-1199
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Forskningsöversikt (refereegranskat)
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| 22. |
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| 23. |
- Olsson, Bob, 1969, et al.
(författare)
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T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.
- 2003
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 9:9, s. 1123-4
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Tidskriftsartikel (refereegranskat)abstract
- Chronic idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder that is characterized by increased platelet destruction and is believed to be autoantibody mediated. In this study, CD3+ T cells from ITP patients had increased expression of genes involved in cell-mediated cytotoxicity. In addition, cytotoxic cell-mediated lysis of autologous platelets was shown in active ITP. Our data suggest that T-cell-mediated cytotoxicity is an alternative mechanism for platelet destruction in ITP.
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| 24. |
- Starck, Göran, et al.
(författare)
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A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity.
- 2008
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 115:7, s. 1051-62
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Tidskriftsartikel (refereegranskat)abstract
- 1H magnetic resonance spectroscopy (1H MRS) studies exploring brain metabolites, especially glutamine + glutamate (Glx), in obsessive compulsive disorder (OCD) are of vital interest for trying to understand more about the pathophysiology of OCD. Therefore, we conducted the present 1H MRS study with the aims of (1) comparing MRS metabolites in a group of adult patients with OCD and a group of healthy controls, and (2) examining the relationship between MRS metabolite concentrations and symptom severity in the patient group. Three brain regions were studied, the right caudate nucleus, the anterior gyrus cinguli and the occipital cortex bilaterally. Since multivariate analysis is a highly useful tool for extraction of 1H MRS data, we applied principal component analysis (PCA) and partial least square projection to latent structures (PLS) to the MRS data. PLS disclosed a strong relationship between several of the metabolites and OCD symptom severity, as measured with Yale-Brown obsessive-compulsive scale (YBOCS): the YBOCS score was found to be positively correlated to caudate creatine, Glx, glutamate, and choline compounds as well as occipital cortex myoinositol, and negatively correlated to occipital cortex Glx. The negative correlation between occipital cortex Glx and YBOCS was the most impressive. PCA did not reveal any tendency for a separation between the patients with OCD and controls with respect to MRS metabolites. The results are discussed in relation to corticostriatothalamocortical feedback and previous observations of poor visuospatial ability in OCD.
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| 25. |
- Svedhem, Sofia, et al.
(författare)
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Subtle differences in dissociation rates of interactions between destabilized human carbonic anhydrase II mutants and immobilized benzenesulfonamide inhibitors probed by a surface plasmon resonance biosensor
- 2001
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Ingår i: Analytical Biochemistry. - : Elsevier BV. - 0003-2697 .- 1096-0309. ; 296:2, s. 188-196
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Tidskriftsartikel (refereegranskat)abstract
- The development of commercial biosensors based on surface plasmon resonance has made possible careful characterization of biomolecular interactions. Here, a set of destabilized human carbonic anhydrase II (HCA II) mutants was investigated with respect to their interaction kinetics with two different immobilized benzenesulfonamide inhibitors. Point mutations were located distantly from the active site, and the destabilization energies were up to 23 kJ/mol. The dissociation rate of wild-type HCA II, as determined from the binding to the inhibitor with higher affinity, was 0.019 s−1. For the mutants, dissociation rates were faster (0.022–0.025 s−1), and a correlation between faster dissociation and a high degree of destabilization was observed. We interpreted these results in terms of increased dynamics of the tertiary structures of the mutants. This interpretation was supported by entropy determinations, showing that the entropy of the native structure significantly increased upon destabilization of the protein molecule. Our findings demonstrate the applicability of modern biosensor technology in the study of subtle details in molecular interaction mechanisms, such as the long-range effect of point mutations on interaction kinetics.
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