Protein misfolding diseases are characterized by deposition of protein aggregates, and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as thioflavin T and Congo red. Herein, the molecular requirements for achieving LCOs able to detect nonthioflavinophilic Aβ aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aβ and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by: 1) replacing thiophene units with selenophene or phenylene moieties, or 2) alternating the anionic substituents along the thiophene backbone. In addition, two asymmetric tetrameric ligands were generated. Overall, the results from this study identified conformational freedom and extended conjugation of the conjugated backbone as crucial determinants for obtaining superior thiophene-based optical ligands for sensitive detection and spectral assignment of disease-associated protein aggregates.
A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer’s disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.
Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant Aβ 1-42 amyloid fibrils and Aβ deposits in brain tissue sections from a transgenic mouse model with Alzheimer's disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiophene-porphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.
BackgroundA previous study has shown no measurable improvement in triage accuracy among physicians attending the Advanced Trauma Life Support (ATLS) course and suggests a curriculum revision regarding triage. Other studies have indicated that cooperative learning helps students acquire knowledge.ObjectiveThe present study was designed to evaluate the effectiveness of trauma cards in triage training for firemen.MethodsEighty-six firemen were randomly assigned into two groups: the trauma card group and the direct instruction group. Both groups received the same 30-min PowerPoint lecture on how to perform triage according to the Sort Assess Lifesaving interventions Treatment and transport (SALT) Mass Casualty Triage Algorithm. In the trauma card group, the participants were divided into groups of 3–5 and instructed to triage 10 trauma victims according to the descriptions on the trauma cards. In the direct instruction group, written forms about the same 10 victims were used and discussed as a continuation of the PowerPoint lecture. Total training time was 60 min for both groups. A test was distributed before and after the educational intervention to measure the individual triage skills. The same test was applied again 6 months later.ResultsThere was a significant improvement in triage skills directly after the intervention and this was sustained 6 months later. No significant difference in triage skills was seen between the trauma card group and the direct instruction group. Previous experience of multi-casualty incidents, years in service, level of education or age did not have any measurable effects on triage accuracy.ConclusionsOne hour of triage training with the SALT Mass Casualty Triage Algorithm was enough to significantly improve triage accuracy in both groups of firemen with sustained skills 6 months later. Further studies on the first assessment on scene versus patient outcome are necessary to provide evidence that this training can improve casualty outcome. The efficacy and validity of trauma cards for disaster management training need to be tested in future studies.
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