182 research outputs found
Stakeholderanalyse
No full textDe toekomst is misschien wel belangrijker dan onze geschiedenis. Of je nu student bent, ambtenaar op een ministerie of in een kleine gemeente, een technostarter, innovatiemanager bij een groot bedrijf, de toekomst is een uiterst belangrijk speelveld.Values and TechnologyTechnology, Policy and Managemen
Backcasting
No full textDe toekomst is misschien wel belangrijker dan onze geschiedenis. Of je nu student bent, ambtenaar op een ministerie of in een kleine gemeente, een technostarter, innovatiemanager bij een groot bedrijf, de toekomst is een uiterst belangrijk speelveld.Values and TechnologyTechnology, Policy and Managemen
Technology assessment
No full textDe toekomst is misschien wel belangrijker dan onze geschiedenis. Of je nu student bent, ambtenaar op een ministerie of in een kleine gemeente, een technostarter, innovatiemanager bij een groot bedrijf, de toekomst is een uiterst belangrijk speelveld.Values and TechnologyTechnology, Policy and Managemen
Emulation of the structure of the Saposin protein fold by a lung surfactant peptide construct of surfactant Protein B
Get PDFThe three-dimensional structure of the synthetic lung Surfactant Protein B Peptide Super Mini-B was determined using an integrative experimental approach, including mass spectrometry and isotope enhanced Fourier-transform infrared (FTIR) spectroscopy. Mass spectral analysis of the peptide, oxidized by solvent assisted region-specific disulfide formation, confirmed that the correct folding and disulfide pairing could be facilitated using two different oxidative structure-promoting solvent systems. Residue specific analysis by isotope enhanced FTIR indicated that the N-terminal and C-terminal domains have well defined α-helical amino acid sequences. Using these experimentally derived measures of distance constraints and disulfide connectivity, the ensemble was further refined with molecular dynamics to provide a medium resolution, residue-specific structure for the peptide construct in a simulated synthetic lung surfactant lipid multilayer environment. The disulfide connectivity combined with the α-helical elements stabilize the peptide conformationally to form a helical hairpin structure that resembles critical elements of the Saposin protein fold of the predicted full-length Surfactant Protein B structure
Secondary Structure Changes in ApoA-I Milano (R173C) Are Not Accompanied by a Decrease in Protein Stability or Solubility.
Get PDFApolipoprotein A-I (apoA-I) is the main protein of high-density lipoprotein (HDL) and a principal mediator of the reverse cholesterol transfer pathway. Variants of apoA-I have been shown to be associated with hereditary amyloidosis. We previously characterized the G26R and L178H variants that both possess decreased stability and increased fibril formation propensity. Here we investigate the Milano variant of apoAI (R173C; apoAI-M), which despite association with low plasma levels of HDL leads to low prevalence of cardiovascular disease in carriers of this mutation. The R173C substitution is located to a region (residues 170 to 178) that contains several fibrillogenic apoA-I variants, including the L178H variant, and therefore we investigated a potential fibrillogenic property of the apoAI-M protein. Despite the fact that apoAI-M shared several features with the L178H variant regarding increased helical content and low degree of ThT binding during prolonged incubation in physiological buffer, our electron microscopy analysis revealed no formation of fibrils. These results suggest that mutations inducing secondary structural changes may be beneficial in cases where fibril formation does not occur
Structural complexity of a composite amyloid fibril
No full textThe molecular structure of amyloid fibrils and the mechanism of their formation are of substantial medical and biological importance, but present an ongoing experimental and computational challenge. An early high-resolution view of amyloid-like structure was obtained on amyloid-like crystals of a small fragment of the yeast prion protein Sup35p: the peptide GNNQQNY. As GNNQQNY also forms amyloid-like fibrils under similar conditions, it has been theorized that the crystal's structural features are shared by the fibrils. Here we apply magic-angle-spinning (MAS) NMR to examine the structure and dynamics of these fibrils. Previously multiple NMR signals were observed for such samples, seemingly consistent with the presence of polymorphic fibrils. Here we demonstrate that peptides with these three distinct conformations instead assemble together into composite protofilaments. Electron microscopy (EM) of the ribbon-like fibrils indicates that these protofilaments combine in differing ways to form striations of variable widths, presenting another level of structural complexity. Structural and dynamic NMR data reveal the presence of highly restricted side-chain conformations involved in interfaces between differently structured peptides, likely comprising interdigitated steric zippers. We outline molecular interfaces that are consistent with the observed EM and NMR data. The rigid and uniform structure of the GNNQQNY crystals is found to contrast distinctly with the more complex structural and dynamic nature of these "composite" amyloid fibrils. These results provide insight into the fibril-crystal distinction and also indicate a necessary caution with respect to the extrapolation of crystal structures to the study of fibril structure and formation
Depression in general practice : underrecognition? Overtreatment? Adequate care!
Get PDFDit proefschrift geeft een optimistisch beeld van de huidige zorg voor depressieve patiënten in de huisartsenpraktijk i.v.m. eerdere literatuur en mediaberichten. We concluderen dat, de zorg voor depressieve patiënten in de eerste lijn in het algemeen adequaat is, d.w.z. in overeenstemming met aanbevelingen uit geldende richtlijnen.
Ruim twee-derde van de depressieve patiënten werd door de huisarts herkend. Patiënten die psychische problemen met de huisarts bespraken, met meer depressieve symptomen en met tevens een angststoornis werden beter herkend. Het atypische symptoom toegenomen eetlust leidde tot slechtere herkenning.
58% van de depressieve patiënten werd verwezen voor psychologische of psychiatrische zorg. Huisartsen hielden de aanbevelingen voor verwijzing uit de richtlijn hierbij in het oog, patiënten met voorkeur voor psychotherapie, met chronische depressie of suïcidale neigingen werden vaker verwezen.
Ook behandeling met antidepressiva schrijven huisartsen volgens de richtlijn voor. Slechts bij 5,4% van de antidepressiva-gebruikers was sprake van overbehandeling. Bovendien was meer dan de helft van deze overbehandelde patiënten met een goede reden gestart, maar te lang doorbehandeld.
Uit een literatuur-review concludeerden wij dat aanbevelingen voor antidepressiva-gebruik gebaseerd zijn op voldoende bewijs v.w.b. acute behandeling en preventie van terugval gedurende enkele maanden, maar niet voor langdurige onderhoudsbehandeling.
Aanbevelingen voor onderhoudsbehandeling worden ook minder goed gevolgd. Het zijn niet, zoals de richtlijn voorschrijft, patiënten met een chronische of recidiverende depressie die onderhoudsbehandeling krijgen. Wel lijken het patiënten met een slechtere prognose: patiënten met tevens een angststoornis of dysthyme stoornis (langdurige ‘milde’ depressie), patiënten die naast antidepressiva ook kalmerende middelen gebruikten en met recente psychiatrische contacten.
Overall this thesis gives an optimistic picture of current care for depressed patients in primary care compared to previous literature and media reports. We conclude that, in general, the care for depressed patients in primary care is in most cases adequate, i.e. in accordance with ruling guideline recommendations.
The general practitioner recognized over two-thirds of depressed patients. Patients discussing psychological problems with the general practitioner, those with more depressive symptoms and with a concurrent anxiety disorder were better recognized. The atypical symptom increased appetite led to worse recognition.
58% of depressed patients were referred for psychological or psychiatric care. General practitioners took guideline recommendations into account in referring; patients with preference for psychotherapy, chronic depression or suicidal tendency were referred more often.
Treatment with antidepressants was also prescribed according to guideline recommendations. In only 5.4% of antidepressant users it could be called overtreatment. Furthermore, over half of these overtreated patients started with a good reason, but were treated too long according to guideline recommendations.
From review of the literature we conclude that guideline recommendations for antidepressant treatment are thoroughly evidence-based for acute treatment and relapse prevention during several months, but not for maintenance treatment.
Recommendations for maintenance treatment are also less often followed. Maintenance users are not, as the guideline prescribes, patients with chronic or recurrent depression. It does however seem that maintenance antidepressant users are those with a worse prognosis such as patients with comorbid dysthymia or anxiety and patients also receiving sedatives or patients with recent psychiatric contacts.
Solid-state NMR studies of peripherally membrane-associated proteins: dealing with dynamics, disorder and dilute conditions
No full textThis chapter reviews applications of solid-state NMR to three peripheral membrane proteins: cardiolipin-bound cytochrome c, phosphatidylinositol-binding Pleckstrin homology domain and membrane-associated myelin basic protein. We describe solutions to common challenges, such as the dynamics of the membrane-bound protein and the preparation of suitable samples with biological relevance. Modern NMR hardware, molecular biology and sample preparation methods pave the way for effective studies of many interesting peripheral membrane proteins by solid-state NMR
Dihedral Angle Measurements for Structure Determination by Biomolecular Solid-State NMR Spectroscopy
Get PDFIn structural studies of immobilized, aggregated and self-assembled biomolecules, solid-state NMR (ssNMR) spectroscopy can provide valuable high-resolution structural information. Among the structural restraints provided by magic angle spinning (MAS) ssNMR the canonical focus is on inter-atomic distance measurements. In the current review, we examine the utility of ssNMR measurements of angular constraints, as a complement to distance-based structure determination. The focus is on direct measurements of angular restraints via the judicious recoupling of multiple anisotropic ssNMR parameters, such as dipolar couplings and chemical shift anisotropies. Recent applications are highlighted, with a focus on studies of nanocrystalline polypeptides, aggregated peptides and proteins, receptor-substrate interactions, and small molecule interactions with amyloid protein fibrils. The review also examines considerations of when and where ssNMR torsion angle experiments are (most) effective, and discusses challenges and opportunities for future applications.</p
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