| 1. |
- Battisti, U. M., et al.
(författare)
-
Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase
- 2023
-
Ingår i: ChemBioChem (Print). - : Wiley. - 1439-4227 .- 1439-7633. ; 24:1
-
Tidskriftsartikel (refereegranskat)abstract
- Enzymes are effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Synthetic modulators of enzymes are useful tools for the study of enzymatic reactions and can provide starting points for the design of new drugs. Here, we report on the discovery of a class of biologically active compounds that covalently modifies lysine residues in human liver pyruvate kinase (PKL), leading to allosteric activation of the enzyme (EC50=0.29 μM). Surprisingly, the allosteric activation control point resides on the lysine residue K282 present in the catalytic site of PKL. These findings were confirmed by structural data, MS/MS experiments, and molecular modelling studies. Altogether, our study provides a molecular basis for the activation mechanism and establishes a framework for further development of human liver pyruvate kinase covalent activators.
|
|
| 2. |
- Dunér, Pontus, et al.
(författare)
-
Antibodies against apoB100 peptide 210 inhibit atherosclerosis in apoE(-/-) mice
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136-3155 amino acid sequence of the LDL protein apolipoprotein B-100 (apoB100) are common in humans and have been associated with less severe atherosclerosis and decreased risk for cardiovascular events in clinical studies. However, whether apoB100 native p210 autoantibodies play a functional role in atherosclerosis is not known. In the present study we immunized apoE(-/-) mice with p210-PADRE peptide to induce an antibody response against native p210. We also injected mice with murine monoclonal IgG against native p210. Control groups were immunized with PADRE peptide alone or with control murine monoclonal IgG. Immunization with p210-PADRE induced an IgG1 antibody response against p210 that was associated with reduced atherosclerotic plaque formation in the aorta and reduced MDA-LDL content in the lesions. Treatment with monoclonal p210 IgG produced a similar reduction in atherosclerosis as immunization with p210-PADRE. Our findings support an atheroprotective role of antibodies against the apoB100 native p210 and suggest that vaccines that induce the expression of native p210 IgG represent a potential therapeutic strategy for lowering cardiovascular risk.
|
|
| 3. |
- Lunde, Ngoc Nguyen, et al.
(författare)
-
Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages
- 2020
-
Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 296, s. 74-82
-
Tidskriftsartikel (refereegranskat)abstract
- Background and aims: We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events.Methods: Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry.Results: In the SUMMIT Malmo cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome.Conclusions: Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.
|
|
| 4. |
- Nain-Perez, Amalyn, et al.
(författare)
-
Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators
- 2023
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 250
-
Tidskriftsartikel (refereegranskat)abstract
- The liver isoform of pyruvate kinase (PKL) has gained interest due to its potential capacity to regulate fatty acid synthesis involved in the progression of non-alcoholic fatty liver disease (NAFLD). Here we describe a novel series of PKL modulators that can either activate or inhibit the enzyme allosterically, from a cryptic site at the interface of two protomers in the tetrameric enzyme. Starting from urolithin D, we designed and synthesised 42 new compounds. The effect of these compounds on PKL enzymatic activity was assessed after incubation with cell lysates obtained from a liver cell line. Pronounced activation of PKL activity, up to 3.8-fold, was observed for several compounds at 10 mu M, while other compounds were prominent PKL inhibitors reducing its activity to 81% at best. A structure-activity relationship identified linear-shaped sulfone-sulfonamides as activators and nonlinear compounds as inhibitors. Crystal structures revealed the conformations of these modulators, which were used as a reference for designing new modulators.
|
|
| 5. |
- Nilsson, Jan, 1963-, et al.
(författare)
-
Development and validation of a new tool measuring nurses self-reported professional competence — The nurse professional competence (NPC) Scale
- 2014
-
Ingår i: Nurse Education Today. - Midlothian, Scotland : Elsevier BV. - 0260-6917 .- 1532-2793. ; 34:4
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To develop and validate a new tool intended for measuring self-reported professional competence among both nurse students prior to graduation and among practicing nurses. The new tool is based on formal competence requirements from the Swedish Board of Health and Welfare, which in turn are based on WHO guidelines. Design: A methodological study including construction of a new scale and evaluation of its psychometric properties. Participants and settings: 1086 newly graduated nurse students from 11 universities/university colleges. Results: The analyses resulted in a scale named the NPC (Nurse Professional Competence) Scale, consisting of 88 items and covering eight factors: “Nursing care”, “Value-based nursing care”, “Medical/technical care”, “Teaching/ learning and support”, “Documentation and information technology”, “Legislation in nursing and safety planning”, “Leadership in and development of nursing care” and “Education and supervision of staff/students”. All factors achieved Cronbach's alpha values greater than 0.70. A second-order exploratory analysis resulted in two main themes: “Patient-related nursing” and “Nursing care organisation and development”. In addition, evidence of known-group validity for the NPC Scale was obtained.
|
|
| 6. |
- Nilsson, Jan, 1963-, et al.
(författare)
-
Nursing in a globalized world : Nursing students with international study experience report higher competence at graduation
- 2014
-
Ingår i: Open Journal of Nursing. - : Scientific Research Publishing, Inc.. - 2162-5336 .- 2162-5344. ; :4, s. 848-858
-
Tidskriftsartikel (refereegranskat)abstract
- Due to globalization, there is a need for nurses with skills and competence in providing safe, competent and culturally appropriate care. The aim of the study was to investigate whether International Study Experiences (ISE) in other countries during basic nursing education had an impact on newly graduated nurses as regards to self-reported competence. Moreover, a second aim was to explore what background factors that facilitated or constituted a hindrance for nursing students to choose to conduct part of their basic nursing education abroad. At 11 Universities/University Colleges (henceforth called Higher Education Institutions [HEIs]) in Sweden, 565 nursing students responded to the Nurse Professional Competence (NPC) Scale. Students with ISE rated their competence significantly higher on three NPC competence areas; “Legislation in nursing and safety planning”, “Leadership and development of nursing” and “Education and supervision of staff/students”. Background factors that significantly seemed to enhance ISE were; living alone, not having children or other commitments, international focus at the HEI and previous international experience. Lack of financial means was reported to prevent students from choosing ISE. The study implies that several background factors are of importance whether students choose ISE or not. ISE during basic nursing education might result in better self-reported competence in leading and developing nursing care, including education of future nurses, and in providing safe care.
|
|
| 7. |
|
|
| 8. |
- Nilsson, Madeleine, et al.
(författare)
-
Patientens delaktighet i val av vårdgivare : En litteratur review
- 2018
-
Ingår i: Nordisk tidsskrift for helseforskning. - : UiT The Arctic University of Norway. - 1504-3614 .- 1891-2982. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- The idea behind care choice is that healthcare providers would be more responsive to patients’ health problems and needs and in doing so compete with increased quality and that patients should be able to choose from this. The question is how patients choose a healthcare provider by themselves. The aim was to describe what affected when patients chose healthcare providers. A literature review was carried out. The results showed that patients’ choice of healthcare providers depended on the following three themes: their own care experiences, caring relationships with staff and service provided by caregivers. The underlying idea of care choice is competition based on quality of care, but the results show that patients make their choices based on other factors as described in the result and therefore improvement can be achieved if focus is placed on being responsive for patient care needs.
|
|
| 9. |
- Wesström, Jan, 1963-
(författare)
-
Sleep Related Movement Disorders : Association with Menopause and Pregnancy
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is known that sleep problems affect people’s wellbeing and has great consequences for public health.Restless legs syndrome (RLS) gives uncomfortable sensations in the legs at rest, leading to an irresistible need for activity. It aggravates in evening and at night. Therefore, RLS provides poorer sleep and can affect quality of life through fatigue, family life and social activities, work, and comorbidity. It is demonstrated a dysfunction of the dopaminergic system in the brain with low levels of dopamine and / or less sensitive dopamine receptors. RLS is more common in women and the prevalence increases with age and during pregnancy.Periodic limb movements are characterized by uncontrolled stretching movements of the legs, especially the toes, ankles, knees and hips during sleep. They last between 0.5 and 5 seconds, and can cause brief awakenings leading to daytime sleepiness. The clinical significance of PLM is rather controversial and PLM is sometimes seen in healthy people with no daytime symptoms.RLS is a subjective diagnosis and translated with the help of questionnaires. PLM however, can objectively be evaluated by polysomnography.Depression is common during and after pregnancy. It is not known whether women with RLS during pregnancy have a higher risk of prenatal or postpartum depression.The aims of this thesis was to to examine the prevalence, associated symptoms and comorbidities, in particular, vasomotor symptoms, menopause, and hormone replacement therapy (HRT) use, among women who suffer from RLS and PLMs. We also evaluated the impact of RLS and PLMs on health related quality of life (HRQoL), and if RLS before and during pregnancy increases the risk of antenatal or postpartum depressive symptoms.Three different poulations were used. Paper 1-3 were cross-sectional and included 5000 resp. 10000 randomly selected women from the general populations of Dalarna and Uppsala County. Questionnaires, polysomnographic recordings, blodtests etc. were used. Paper 4 was a longitudinal cohort study where 1428 pregnant women in Uppsala County were followed.In summary, data included in this thesis points out that RLS and PLMs are more common in women with estrogendeficiency-related symptoms of menopause. RLS-positive women had an impaired mental HRQoL compared to RLS-negative women and more often suffered from comorbidities. Data also revealed that women with RLS before and during pregnancy are at increased risk for depression during and after pregnancy.
|
|
| 10. |
- Algaba, Juan-Carlos, et al.
(författare)
-
Broadband Multi-wavelength Properties of M87 during the 2017 Event Horizon Telescope Campaign
- 2021
-
Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 911:1
-
Forskningsöversikt (refereegranskat)abstract
- In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109 M o˙. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87's spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded.
|
|
