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| 3. |
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| 4. |
- Solmi, M, et al.
(författare)
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- 2022
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Ingår i: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 299, s. 367-376
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 6. |
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| 7. |
- Enkovaara, J., et al.
(författare)
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Electronic structure calculations with GPAW : a real-space implementation of the projector augmented-wave method
- 2010
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Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 22:25, s. 253202-
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Forskningsöversikt (refereegranskat)abstract
- Electronic structure calculations have become an indispensable tool in many areas of materials science and quantum chemistry. Even though the Kohn-Sham formulation of the density-functional theory (DFT) simplifies the many-body problem significantly, one is still confronted with several numerical challenges. In this article we present the projector augmented-wave (PAW) method as implemented in the GPAW program package (https://wiki.fysik.dtu.dk/gpaw) using a uniform real-space grid representation of the electronic wavefunctions. Compared to more traditional plane wave or localized basis set approaches, real-space grids offer several advantages, most notably good computational scalability and systematic convergence properties. However, as a unique feature GPAW also facilitates a localized atomic-orbital basis set in addition to the grid. The efficient atomic basis set is complementary to the more accurate grid, and the possibility to seamlessly switch between the two representations provides great flexibility. While DFT allows one to study ground state properties, time-dependent density-functional theory (TDDFT) provides access to the excited states. We have implemented the two common formulations of TDDFT, namely the linear-response and the time propagation schemes. Electron transport calculations under finite-bias conditions can be performed with GPAW using non-equilibrium Green functions and the localized basis set. In addition to the basic features of the real-space PAW method, we also describe the implementation of selected exchange-correlation functionals, parallelization schemes, Delta SCF-method, x-ray absorption spectra, and maximally localized Wannier orbitals.
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| 8. |
- Kjaerulff, T. M., et al.
(författare)
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Patterns of finasteride use in the male populations of four Nordic countries: A cross-national drug utilization study
- 2016
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Ingår i: Scandinavian Journal of Urology. - : Informa UK Limited. - 2168-1805 .- 2168-1813. ; 50:3, s. 220-227
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Tidskriftsartikel (refereegranskat)abstract
- Objective Finasteride 5 mg is a drug used to treat prostate hyperplasia. Little is known about its pattern of usage. This cross-national analysis of individual-level data from Denmark, Finland, Norway and Sweden was undertaken to appraise its usage and describe cross-national differences. Materials and methods Individual-level data from nationwide prescription registers in Denmark (1995-2009), Finland (1997-2010), Norway (2004-2009) and Sweden (July 2005-2011) were used to examine cross-national finasteride utilization patterns in the adult male population (>= 15 years). The study presents period prevalences, incidence rates, waiting time distributions and Lorenz curves. Results During the study period, 295,620 men had at least one prescription redemption of finasteride 5 mg, and there were approximately 3 million dispensing events of finasteride prescriptions in the four Nordic countries. Different patterns of finasteride use were observed among the four Nordic countries. The period prevalence was markedly higher in Finland and Sweden than in Denmark and Norway. In 2009, period prevalences were 18.2/1000 males in Finland and 12.0/1000 males in Sweden compared to 6.7/1000 males in Norway and 4.9/1000 males in Denmark. Incidence rates of finasteride use for Finland, Norway and Sweden were about three times that for Denmark in 2008-2009. Long-term use of finasteride was found in all four Nordic countries with a high ratio between prevalent and incident users. Conclusion Despite resemblances regarding political systems and healthcare services in the Nordic countries, differences in finasteride utilization were found across Denmark, Finland, Norway and Sweden. RAMS P, 1994, BRITISH MEDICAL JOURNAL, V308, P929
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| 9. |
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| 10. |
- Mair, J., et al.
(författare)
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The clinical approach to diagnosing peri-procedural myocardial infarction after percutaneous coronary interventions according to the fourth universal definition of myocardial infarction - from the study group on biomarkers of the European Society of Cardiology (ESC) Association for Acute CardioVascular Care (ACVC)
- 2022
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Ingår i: Biomarkers. - : Informa UK Limited. - 1354-750X .- 1366-5804. ; 27:5, s. 407-417
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Tidskriftsartikel (refereegranskat)abstract
- Purpose This review intends to illustrate basic principles on how to apply the Fourth Universal Definition of Myocardial Infarction (UDMI) for the diagnosis of peri-procedural myocardial infarction (MI) after percutaneous coronary interventions (PCI) in clinical practice. Methods and Results Review of routine case-based events. Increases in cardiac troponin (cTn) concentrations are common after elective PCI in patients with chronic coronary syndrome (CCS). Peri-procedural PCI-related MI (type 4a MI) in CCS patients should be diagnosed in cases of major peri-procedural acute myocardial injury indicated by an increase in cTn concentrations of >5-times the 99th percentile upper reference limit (URL) together with evidence of new peri-procedural myocardial ischaemia as demonstrated by electrocardiography (ECG), imaging, or flow-limiting peri-procedural complications in coronary angiography. Measurement of cTn baseline concentrations before elective PCI is useful. In patients presenting with acute MI undergoing PCI, peri-procedural increases in cTn concentrations are usually due to their index presentation and not PCI-related, apart from obvious major peri-procedural complications, such as persistent occlusion of a large side branch or no-reflow after stent implantation. Conclusion The distinction between type 4a MI, PCI-related acute myocardial injury, and chronic myocardial injury can be challenging in individuals undergoing PCI. Careful integration of all available clinical data is essential for correct classification.
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| 11. |
- Meijer, M., et al.
(författare)
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Finasteride treatment and male breast cancer: a register-based cohort study in four Nordic countries
- 2018
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 7:1, s. 254-260
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Tidskriftsartikel (refereegranskat)abstract
- A potential link has been suggested between dispensed finasteride and increased risk of male breast cancer (MBC). Due to the rare occurrence of MBC, it remains to be established if such a relationship exists. The purpose of this study was to combine nationwide registers in four countries to assess the potential association between dispensed finasteride and MBC. A cohort of all males with dispensed finasteride in Denmark, Finland, Norway, and Sweden (1,365,088 person years) was followed up for up to 15years for breast cancer, and compared to a cohort of males unexposed to finasteride. Individual-level register data included country, dates of dispensed finasteride, MBC diagnosis, and death. Incidence rate ratios (IRRs) were estimated using a generalized linear model with a Poisson distribution. An increased risk of MBC was found among finasteride users (IRR=1.44, 95% confidence interval [95% CI]=1.11-1.88) compared to nonusers. The IRR increased to 1.60 (95% CI=1.20-2.13) when users in Norway and Sweden with short follow-up time were excluded. The highest IRR was seen among men with medium duration of dispensed finasteride, medium accumulated consumption of finasteride, and among men with first dispensed finasteride prescription 1-3years prior to diagnosis. The analyses suggested possible ascertainment bias and did not support a clear relationship between dispensed finasteride and MBC. In conclusion, a significant association between dispensed finasteride and MBC was identified. However, due to limited data for adjustment of potential confounding and surveillance bias in the present study, further research is needed to confirm these results.
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| 12. |
- Mueller, C., et al.
(författare)
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Cardiovascular biomarkers in patients with COVID-19
- 2021
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Ingår i: European Heart Journal-Acute Cardiovascular Care. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 10:3, s. 310-319
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Tidskriftsartikel (refereegranskat)abstract
- The coronavirus disease 2019 (COVID-19) pandemic has increased awareness that severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) may have profound effects on the cardiovascular system. COVID-19 often affects patients with pre-existing cardiac disease, and may trigger acute respiratory distress syndrome (ARDS), venous thromboembolism (VTE), acute myocardial infarction (AMI), and acute heart failure (AHF). However, as COVID-19 is primarily a respiratory infectious disease, there remain substantial uncertainty and controversy whether and how cardiovascular biomarkers should be used in patients with suspected COVID-19. To help clinicians understand the possible value as well as the most appropriate interpretation of cardiovascular biomarkers in COVID-19, it is important to highlight that recent findings regarding the prognostic role of cardiovascular biomarkers in patients hospitalized with COVID-19 are similar to those obtained in studies for pneumonia and ARDS in general. Cardiovascular biomarkers reflecting pathophysiological processes involved in COVID-19/pneumonia and its complications have a role evaluating disease severity, cardiac involvement, and risk of death in COVID-19 as well as in pneumonias caused by other pathogens. First, cardiomyocyte injury, as quantified by cardiac troponin concentrations, and haemodynamic cardiac stress, as quantified by natriuretic peptide concentrations, may occur in COVID-19 as in other pneumonias. The level of those biomarkers correlates with disease severity and mortality. Interpretation of cardiac troponin and natriuretic peptide concentrations as quantitative variables may aid in risk stratification in COVID-19/pneumonia and also will ensure that these biomarkers maintain high diagnostic accuracy for AMI and AHF. Second, activated coagulation as quantified by D-dimers seems more prominent in COVID-19 as in other pneumonias. Due to the central role of endothelitis and VTE in COVID-19, serial measurements of D-dimers may help physicians in the selection of patients for VTE imaging and the intensification of the level of anticoagulation from prophylactic to slightly higher or even therapeutic doses.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Kjaerulff, T. M., et al.
(författare)
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Finasteride Use and Risk of Male Breast Cancer: A Case-Control Study Using Individual-Level Registry Data from Denmark, Finland, and Sweden
- 2019
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1055-9965. ; 28:5, s. 980-986
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Tidskriftsartikel (refereegranskat)abstract
- Background: In case reports, concerns have been raised as to whether finasteride use increases the risk of male breast cancer. Previous epidemiologic evidence on the potential link is conflicting. This study aimed to assess whether an association between finasteride use and male breast cancer exists after accounting for potential confounders. Methods: The source population consisted of all men (similar to 35 years) from Denmark (1995-2014), Finland (1997-2013), and Sweden (2005-2014). Cases with incident male breast cancer were identified in the cancer registries and matched with 50 density-sampled, age, and country-matched male population controls per case. Exposure information on finasteride use was derived from the prescription registries. Potential confounders were identified using the directed acyclic graph methodology and measured by use of information from nation-wide registries. Results: The study population comprised 1,005 male breast cancer cases and 43,058 controls. Confounder-adjusted odds of finasteride exposure were not statistically significantly increased [OR, 1.09; 95% confidence interval (CI), 0.77-1.54] in breast cancer cases relative to controls. There was no evidence of a dose-response relationship, as the group with greatest exposure to finasteride was associated with lowest OR of male breast cancer [OR, 0.72 (95% CI, 0.40-1.30)]. Sensitivity analyses did not reveal marked changes in results with different exposure definitions or for specific subgroups. Conclusions: Results from this study provided no evidence that finasteride use was associated with male breast cancer. Impact: This large confounder-adjusted study supports the view that exposure to finasteride is not associated materially with male breast cancer risk.
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| 18. |
- Mair, J., et al.
(författare)
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Application of the fourth universal definition of myocardial infarction in clinical practice
- 2020
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Ingår i: Biomarkers. - : Informa UK Limited. - 1354-750X .- 1366-5804. ; 25:4, s. 322-330
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The Fourth Universal Definition of Myocardial Infarction (MI) has highlighted the different pathophysiological mechanisms that may lead to ischaemic and non-ischaemic myocardial injury and has emphasised that the diagnosis of myocardial infarction requires the presence of acute myocardial ischaemia in the setting of acute myocardial injury. This case based review intends to illustrate basic principles on how to apply this new, revised definition in clinical practice. Methods and Results: The distinction between different types of MIs (type 1 or type 2) and the delineation of MI from acute non-ischaemic myocardial injury may be challenging in individual patients, which is illustrated by presenting and discussing real-life routine cases. Conclusions: Type 1 MI is a consequence of coronary plaque rupture or erosion with intracoronary thrombus formation that is usually apparent on coronary angiography. Plausible triggering mechanisms causing myocardial oxygen supply/demand mismatch must be identified for the diagnosis of type 2 MI and its treatment should focus initially on management of the underlying disease attributable to acute myocardial ischaemia.
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| 19. |
- Mair, J., et al.
(författare)
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How is cardiac troponin released from injured myocardium?
- 2018
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Ingår i: European Heart Journal-Acute Cardiovascular Care. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 7:6, s. 553-560
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac troponin I and cardiac troponin T are nowadays the criterion biomarkers for the laboratory diagnosis of acute myocardial infarction due to their very high sensitivities and specificities for myocardial injury. However, still many aspects of their degradation, tissue release and elimination from the human circulation are incompletely understood. Myocardial injury may be caused by a variety of different mechanisms, for example, myocardial ischaemia, inflammatory and immunological processes, trauma, drugs and toxins, and myocardial necrosis is preceded by a substantial reversible prelethal phase. Recent experimental data in a pig model of myocardial ischaemia demonstrated cardiac troponin release into the circulation from apoptotic cardiomyocytes as an alternative explanation for clinical situations with increased cardiac troponin without any other evidence for myocardial necrosis. However, the comparably lower sensitivities of all currently available imaging modalities, including cardiac magnetic resonance imaging for the detection of particularly non-focal myocardial necrosis in patients, has to be considered for cardiac troponin test result interpretation in clinical settings without any other evidence for myocardial necrosis apart from increased cardiac troponin concentrations as well.
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| 20. |
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| 21. |
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| 22. |
- Sengupta, K., et al.
(författare)
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Utilization of etoricoxib in dental patients in the Nordic countries: a population-based register study
- 2019
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Ingår i: Acta Odontologica Scandinavica. - : Informa UK Limited. - 0001-6357 .- 1502-3850. ; 77:8, s. 584-591
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Tidskriftsartikel (refereegranskat)abstract
- Background: Etoricoxib is a second-generation cyclooxygenase-2-inhibitor approved in 2012 for short-term treatment of pain associated with dental surgery. Objectives: To evaluate etoricoxib utilization in dental patients in the Nordic countries, including its off-label use. Methods: The entire populations of Denmark, Finland, Sweden and Norway with etoricoxib prescriptions written by dentists and dispensed in 2012–2014 were evaluated using national register data. Nationwide estimates of etoricoxib utilization were generated according to year, gender, age, dose and package size. Off-label use in paediatric patients, prescribed doses >90 mg/day or for dental contacts not associated with surgical procedures, and concomitant administration with anticoagulants were evaluated. Results: Utilization of etoricoxib for dental pain was low (1615 prescriptions: Finland, 907; Sweden, 359; Norway, 337; Denmark, 12). Overall, 70% of the prescriptions were without an associated dental procedure. Moreover, 58%, 55%, 10% and 58% of the prescriptions in Denmark, Finland, Sweden and Norway, respectively, were for >90 mg/day doses. Few paediatric prescriptions were dispensed (n < 10), and only a small overlap (n = 21) was observed between etoricoxib and anticoagulant prescriptions. Conclusions: Given the low overall number of prescriptions, it is unlikely that off-label use of etoricoxib within dentistry in the Nordic countries is an important public health concern. © 2019, © 2019 Acta Odontologica Scandinavica Society.
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| 23. |
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| 24. |
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| 25. |
- Tubaro, M., et al.
(författare)
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Pre-hospital treatment of STEMI patients. A scientific statement of the working group acute cardiac care of the European society of cardiology
- 2011
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Ingår i: Acute Cardiac Care. - : Informa Healthcare. - 1748-2941 .- 1748-295X. ; 13:2, s. 56-67
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Tidskriftsartikel (refereegranskat)abstract
- In ST-elevation myocardial infarction (STEMI) the pre-hospital phase is the most critical, as the administration of the most appropriate treatment in a timely manner is instrumental for mortality reduction. STEMI systems of care based on networks of medical institutions connected by an efficient emergency medical service are pivotal. The first steps are devoted to minimize the patients delay in seeking care, rapidly dispatch a properly staffed and equipped ambulance to make the diagnosis on scene, deliver initial drug therapy and transport the patient to the most appropriate (not necessarily the closest) cardiac facility. Primary PCI is the treatment of choice, but thrombolysis followed by coronary angiography and possibly PCI is a valid alternative, according to patients baseline risk, time from symptoms onset and primary PCI-related delay. Paramedics and nurses have an important role in pre-hospital STEMI care and their empowerment is essential to increase the eff ectiveness of the system. Strong cooperation between cardiologists and emergency medicine doctors is mandatory for optimal pre-hospital STEMI care. Scientific societies have an important role in guideline implementation as well as in developing quality indicators and performance measures; health care professionals must overcome existing barriers to optimal care together with political and administrative decision makers.
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| 26. |
- Wachtell, K., et al.
(författare)
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Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death: the LIFE Study
- 2007
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 1524-4539 .- 0009-7322. ; 116:7, s. 700-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sudden cardiac death (SCD) occurs more often in patients with ECG left ventricular (LV) hypertrophy. However, whether LV hypertrophy regression is associated with a reduced risk of SCD remains unclear. METHODS AND RESULTS: The Losartan Intervention for End Point Reduction in Hypertension (LIFE) study included 9193 patients 55 to 80 years of age with essential hypertension and ECG LV hypertrophy by gender-adjusted Cornell product (CP) (RaVL+SV(3) [+6 mm in women]). QRS duration>2440 mm x ms) and/or Sokolow-Lyon voltage (SLV) (SV1+RV(5/6)>38 mm). During follow-up (mean, 4.8 years), 190 patients (2%) experienced SCD. In time-dependent Cox analyses, absence of in-treatment LV hypertrophy was associated with a decreased risk of SCD: every 1-SD-lower in-treatment CP (1050 mm x ms) was associated with a 28% lower risk of SCD (hazard ratio [HR], 0.72; 95% CI, 0.66 to 0.79) and 1-SD-lower SLV (10.5 mm) with a 26% lower risk (HR, 0.74; 95% CI, 0.65 to 0.84). After adjustment for time-varying systolic and diastolic blood pressures, treatment allocation, age, gender, baseline Framingham risk score, ECG strain, heart rate, urine albumin/creatinine ratio, smoking, diabetes, congestive heart failure, coronary heart disease, atrial fibrillation, and occurrence of myocardial infarction, atrial fibrillation, heart failure, and noncardiovascular death, both in-treatment CP and SLV remained predictive of SCD: each 1-SD-lower CP was associated with a 19% lower risk of SCD (HR, 0.81; 95% CI, 0.73 to 0.90) and 1-SD-lower SLV with an 18% lower risk (HR, 0.82; 95% CI, 0.70 to 0.98). Absence of in-treatment LV hypertrophy by both SLV and CP was associated with a 30% lower risk of SCD (HR, 0.70; 95% CI, 0.54 to 0.92). CONCLUSIONS: Absence of in-treatment ECG LV hypertrophy is associated with reduced risk of SCD independently of treatment modality, blood pressure reduction, prevalent coronary heart disease, and other cardiovascular risk factors in hypertensive patients with LV hypertrophy.
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| 27. |
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| 28. |
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| 29. |
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| 30. |
- Clabbers, Max T. B., et al.
(författare)
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MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- MyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MALTIR) forms filaments in vitro and induces formation of crystalline higher-order assemblies of the MyD88 TIR domain (MyD88TIR). These crystals are too small for conventional X-ray crystallography, but are ideally suited to structure determination by microcrystal electron diffraction (MicroED) and serial femtosecond crystallography (SFX). Here, we present MicroED and SFX structures of the MyD88TIR assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MALTIR. We demonstrate via mutagenesis that the MyD88TIR assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88TIR. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.
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| 31. |
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| 32. |
- Cromhout, Pernille F, et al.
(författare)
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Supplementing prediction by EuroSCORE with social and patient-reported measures among patients undergoing cardiac surgery.
- 2021
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Ingår i: Journal of cardiac surgery. - : Hindawi Limited. - 1540-8191 .- 0886-0440. ; 36:2, s. 509-521
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Tidskriftsartikel (refereegranskat)abstract
- The risk of poor outcomes is traditionally attributed to biological and physiological processes in cardiac surgery. However, evidence exists that other factors, such as emotional, behavioral, social, and functional, are predictive of poor outcomes. Objectives were to evaluate the predictive value of several emotional, social, functional, and behavioral factors on four outcomes: death within 90 days, prolonged stay in intensive care, prolonged hospital admission, and readmission within 90 days following cardiac surgery.This prospective study included adults undergoing cardiac surgery 2013-2014, including information on register-based socioeconomic factors and self-reported health in a nested subsample. Logistic regression analyses to determine the association and incremental value of each candidate predictor variable were conducted. Multiple regression analyses were used to determine the incremental value of each candidate predictor variable, as well as discrimination and calibration based on the area under the curve (AUC) and Brier score.Of 3217 patients, 3% died, 9% had prolonged intensive care stay, 51% had prolonged hospital admission, and 39% were readmitted to hospital. Patients living alone (odds ratio, 1.19; 95% confidence interval, 1.02-1.38), with lower educational levels (1.27; 1.04-1.54) and low health-related quality of life (1.43; 1.02-2.01) had prolonged hospital admission. Analyses revealed living alone as predictive of prolonged intensive care unit (ICU) stay (Brier, 0.08; AUC, 0.68), death (0.03; 0.71), and prolonged hospital admission (0.24; 0.62).Living alone was found to supplement EuroSCORE in predicting death, prolonged hospital admission, and prolonged ICU stay following cardiac surgery. Low educational level and impaired health-related quality of life were, furthermore, predictive of prolonged hospital admission.
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| 33. |
- Fischer, M., et al.
(författare)
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Controlled generation of luminescent centers in hexagonal boron nitride by irradiation engineering
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Luminescent centers in the two-dimensional material hexagonal boron nitride have the potential to enable quantum applications at room temperature. To be used for applications, it is crucial to generate these centers in a controlled manner and to identify their microscopic nature. Here, we present a method inspired by irradiation engineering with oxygen atoms. We systematically explore the influence of the kinetic energy and the irradiation fluence on the generation of luminescent centers. We find modifications of their density for both parameters, while a fivefold enhancement is observed with increasing fluence. Molecular dynamics simulations clarify the generation mechanism of these centers and their microscopic nature. We infer that VNCB and V-B are the most likely centers formed. Ab initio calculations of their optical properties show excellent agreement with our experiments. Our methodology generates quantum emitters in a controlled manner and provides insights into their microscopic nature.
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| 34. |
- Gersing, Sarah K., et al.
(författare)
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Mapping the degradation pathway of a disease-linked aspartoacylase variant
- 2021
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:4
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Tidskriftsartikel (refereegranskat)abstract
- Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we use ASPA C152W as a model to investigate the degradation pathway of a disease-causing protein variant. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution interferes with the de novo folding pathway resulting in increased proteasomal degradation before reaching its stable conformation. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In addition, the disaggregase Hsp104 facilitated refolding of aggregated ASPA C152W, while Cdc48 mediated degradation of insoluble ASPA protein. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. Our findings underscore the use of yeast to determine the protein quality control components involved in the degradation of human pathogenic variants in order to identify potential therapeutic targets. Author summary Canavan disease is a fatal neurodegenerative disorder which is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene. Although the molecular mechanism of most disease-causing substitutions remains to be examined, some variants have been suggested to cause the loss-of-function phenotype by perturbing the structural stability of ASPA. So far the cellular fate of these variants have not been examined. Here we examine the stability and degradation pathways of the disease-causing ASPA variant C152W. In yeast cells, ASPA C152W showed decreased steady-state protein levels as a result of increased proteasomal turnover. Our molecular dynamics simulations showed that the C152W substitution did not globally perturb the native structure of ASPA. Instead we propose that ASPA C152W is targeted by the protein quality control system during de novo folding. Specifically, we found that the molecular chaperone Hsp70, its co-chaperone Hsp110, and the E3 ubiquitin-protein ligase Ubr1 promote degradation of ASPA C152W. When we expressed ASPA C152W in cultured human cells, we found that Hsp70 and Hsp110 similarly mediated degradation. Therefore, we propose that Hsp110 should be further examined as a potential therapeutic target in Canavan disease and other protein misfolding diseases.
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| 35. |
- Hao, Xian, et al.
(författare)
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Direct measurement and modulation of single-molecule coordinative bonding forces in a transition metal complex
- 2013
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Coordination chemistry has been a consistently active branch of chemistry since Werner’s seminal theory of coordination compounds inaugurated in 1893, with the central focus on transition metal complexes. However, control and measurement of metal–ligand interactions at the single-molecule level remain a daunting challenge. Here we demonstrate an interdisciplinary and systematic approach that enables measurement and modulation of the coordinative bonding forces in a transition metal complex. Terpyridine is derived with a thiol linker, facilitating covalent attachment of this ligand on both gold substrate surfaces and gold-coated atomic force microscopy tips. The coordination and bond breaking between terpyridine and osmium are followed in situ by electrochemically controlled atomic force microscopy at the single-molecule level. The redox state of the central metal atom is found to have a significant impact on the metal–ligand interactions. The present approach represents a major advancement in unravelling the nature of metal–ligand interactions and could have broad implications in coordination chemistry.
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| 36. |
- Knot, J, et al.
(författare)
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How to set up an effective national primary angioplasty network : Lessons learned from five European countries
- 2009
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Ingår i: EuroIntervention. - 1774-024X. ; 3:299, s. 301-309
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Percutaneous coronary interventions (PCI) are used to treat acute and chronic forms of coronary artery disease. While in chronic forms the main goal of PCI is to improve the quality of life, in acute coronary syndromes (ACS) timely PCI is a life-saving procedure - especially in the setting of ST-elevation myocardial infarction (STEMI). The aim of this study was to describe the experience of countries with successful nationwide implementation of PCI in STEMI, and to provide general recommendations for other countries. METHODS AND RESULTS: The European Association of Percutaneous Cardiovascular Interventions (EAPCI) recenty launched the Stent For Life Initiative (SFLI). The initial phase of this pan-European project was focused on the positive experience of five countries to provide the best practice examples. The Netherlands, the Czech Republic, Sweden, Denmark and Austria were visited and the logistics of ACS treatment was studied. Public campaigns improved patient access to acute PCI. Regional networks involving emergency medical services (EMS), non-PCI hospitals and PCI centres are useful in providing access to acute PCI for most patients. Direct transfer from the first medical contact site to the cathlab is essential to minimise the time delays. Cathlab staff work is organised to provide acute PCI services 24 hours a day / seven days a week (24/7). Even in those regions where thrombolysis is still used due to long transfer distances to PCI, patients should still be transferred to a PCI centre (after thrombolysis). The highest risk non-ST elevation acute myocardial infarction patients should undergo emergency coronary angiography within two hours of hospital admission, i.e. similar to STEMI patients. CONCLUSIONS: Three realistic goals for other countries were defined based on these experiences: 1) primary PCI should be used for >70% of all STEMI patients, 2) primary PCI rates should reach >600 per million inhabitants per year and 3) existing PCI centres should treat all their STEMI patients by primary PCI, i.e. should offer a 24/7 service
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| 37. |
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- Norgaard, B. L., et al.
(författare)
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Long term risk stratification of patients with acute coronary syndromes: characteristics of troponin T testing and continuous ST segment monitoring
- 2004
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Ingår i: Heart. - 1468-201X. ; 90:7, s. 739-44
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the long term prognostic characteristics of troponin T testing and continuous multi-lead ST segment monitoring in combination with clinical and 12 lead ECG risk indicators in patients with acute coronary syndromes (ACS). PATIENTS AND DESIGN: Patients with suspected ACS (n = 213) were studied. Troponin T was analysed in blood samples collected during the first 12 hours after admission. Continuous vectorcardiography ST segment monitoring was performed for 24 hours and the number of ST vector magnitude episodes was registered. Patients were followed up for a median of 28 months. The end point was a composite of cardiac death and acute myocardial infarction. RESULTS: Thirty eight (18%) patients reached the composite end point. The median (interquartile range) time from study inclusion to the time of the composite end point was longer for patients predicted to be at risk by troponin T testing (n = 27) than for those predicted to be at risk by ST segment monitoring (n = 20) (8.4 (0.2-15) months v 0.3 (0.1-4.3) months, p = 0.04). Significant univariate predictors of the composite end point were age > or = 65 years, diabetes, previous myocardial infarction, congestive heart failure, use of beta blockers or diuretics at admission, 12 lead ECG ST segment depression at admission, troponin T concentration > or = 0.10 microg/l, and > or = 1 ST vector magnitude episodes. Age > or = 65 years, previous myocardial infarction, and troponin T concentration > or = 0.10 microg/l provided independent prognostic information after multivariate analysis of potential risk variables. The prognostic value of transient ischaemic episodes in ACS seems to be confined to the short term. CONCLUSIONS: Both biochemical and continuous ECG markers reflect an increased risk for patients with ACS; however, the methods exhibit different temporal risk characteristics.
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