Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau.

Tau pathology in Alzheimer's disease is intimately linked to the deposition of proteinacious filaments, which akin to infectious prions, have been proposed to spread via seeded conversion. Here we use double electron-electron resonance (DEER) spectroscopy in combination with extensive computational analysis to show that filaments of three- (3R) and four-repeat (4R) tau are conformationally distinct. Distance measurements between spin labels in the third repeat, reveal tau amyloid filaments as ensembles of known ß-strand-turn-ß-strand U-turn motifs. Whereas filaments seeded with 3R tau are structurally homogeneous, filaments seeded with 4R tau are heterogeneous, composed of at least three distinct conformers. These findings establish a molecular basis for the seeding barrier between different tau isoforms and offer a new powerful approach for investigating the composition and dynamics of amyloid fibril ensembles.

Investigation of factors affecting COVID-19 vaccine acceptance among communities of universities in the United Arab Emirates.

The COVID-19 pandemic affected the lives of people living across the world and the development of vaccines against SARS-CoV-2 is considered to be one of the most promising solutions to contain the COVID-19 pandemic. In several countries, we are witnessing hesitancy toward COVID-19 vaccines, which is a complex phenomenon influenced by a variety of factors. A cross-sectional study was performed to comprehensively investigate the impact of factors like demography, COVID-19 pandemic-induced behavior, and vaccine attitude on COVID-19 vaccine acceptance (VA) among communities of five different universities in the United Arab Emirates (UAE). To investigate the effect of demography and COVID-19 pandemic-induced behavioral factors, Analysis of Variance was perfomed. The effect of COVID-19 vaccine attitudes on COVID-19 VA was examined through partial least squares-structural equations modeling. The results of the study showed no difference among the population in accepting COVID-19 vaccines due to their demographic factors. The effect of pandemic-induced behavioral factors on COVID-19 VA suggested that the people of UAE accepted COVID-19 vaccines irrespective of the movement and travel restrictions imposed due to the pandemic. The results on the effect of vaccine attitudes on COVID-19 VA showed that vaccine benefit attitudes, safety concerns, and trust in health-care professionals (TrHP) were found to be significant factors in VA. Furthermore, TrHP was found to reduce the negative effect of safety concerns related to COVID-19 VA. The findings broadly highlight that COVID-19 VA in the UAE was not hampered by demographic factors and the pandemic-induced behavioral constraints. The study also showed that people with co-morbidities had lower level of COVID-19 VA than people with no co-morbidities. To improve COVID-19 VA, the perceived benefits with COVID-19 vaccine and TrHP must be enhanced and simultaneously safety concerns of the vaccines need to be addressed.

Variations in filament conformation dictate seeding barrier between three- and four-repeat tau.

Tau filaments are the pathological hallmark of >20 neurodegenerative diseases including Alzheimer's disease. Six tau isoforms exist that can be grouped into 4-repeat (4R) tau and 3-repeat (3R) tau based on the presence or absence of the second of four microtubule binding repeats. Recent evidence suggests that tau filaments can transfer between cells and spread through the brain. Here we demonstrate in vitro that seeded filament growth, a prerequisite for tau spreading, is crucially dependent on the isoform composition of individual seeds. Seeds of 3R tau and 3R/4R tau recruit both types of isoforms. Seeds of 4R tau recruit 4R tau, but not 3R tau, establishing an asymmetric barrier. Conformational templating of 4R tau onto 3R tau seeds eliminates this barrier, giving rise to a new type of tau filament. These findings provide fundamental mechanistic insights into the seeding, propagation, and diversification of tau filaments.

Three- and four-repeat Tau coassemble into heterogeneous filaments: an implication for Alzheimer disease.

Tau filaments are the pathological hallmark of numerous neurodegenerative diseases including Alzheimer disease, Pick disease, and progressive supranuclear palsy. In the adult human brain, six isoforms are expressed that differ by the presence or absence of the second of four semiconserved repeats. As a consequence, half of the tau isoforms have three repeats (3R tau), whereas the other half of the isoforms have four repeats (4R tau). Tauopathies can be characterized based on the isoform composition of their filaments. Alzheimer disease filamentous inclusions contain all isoforms. Pick disease filaments contain 3R tau. Progressive supranuclear palsy filaments contain 4R tau. Here, we used site-directed spin labeling of recombinant tau in conjunction with electron paramagnetic resonance spectroscopy to obtain structural insights into these filaments. We find that filaments of 4R tau and 3R tau share a highly ordered core structure in the third repeat with parallel, in-register arrangement of ß-strands. This structure is conserved regardless of whether full-length isoforms (htau40 and htau23) or truncated constructs (K18 and K19) are used. When mixed, 3R tau and 4R tau coassemble into heterogeneous filaments. These filaments share the highly ordered core in the third repeat; however, they differ in their overall composition. Our findings indicate that at least three distinct types of filaments exist: homogeneous 3R tau, homogeneous 4R tau, and heterogeneous 3R/4R tau. These results suggest that individual filaments found in Alzheimer disease are structurally distinct from those in the 3R and 4R tauopathies.

Antecedents of patients' trust in pharmacists: empirical investigation in the United Arab Emirates.

OBJECTIVES: To empirically identify the antecedents that influence patients trust in pharmacists. METHODS: A survey was conducted among 500 patients who visited community pharmacies in Al Ain City, United Arab Emirates. The questionnaire included the measures for constructs such as patients' perception of pharmacist communication, pharmacists' technical competence, medication self-efficacy, satisfaction with pharmacy and trust in pharmacists. KEY FINDINGS: The data were analysed using partial least-squares structural equation modelling approach to check the validity and reliability of the measures and to validate the proposed hypotheses of the study. Pharmacist communication, pharmacists' technical competence, satisfaction with pharmacy and patients' medication self-efficacy were found to significantly influence patients' trust in pharmacists. CONCLUSION: This study is the first one that has empirically identified the antecedents of trust in pharmacists. The study has established that patients' perception of pharmacist communication and pharmacists' technical competence positively influence trust in pharmacists as antecedents but not constitute trust itself as had been found in the previous research. Apart from enhancing pharmacists' technical competence and communication, the pharmacy organizations and policymakers should improve patients' satisfaction with pharmacy and patients' medication self-efficacy to enhance patients' trust in pharmacists.

Increased expression of PSA mRNA during brachytherapy in peripheral blood of patients with prostate cancer.

OBJECTIVES: To determine the extent of iatrogenic tumor cell dissemination during brachytherapy by assessing prostate-specific antigen (PSA) mRNA expression in circulating prostate tumor cells using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The instrumentation used in the radioisotope seed placement of the prostate causes trauma to blood vessels and provides a vascular access for tumor cells that can lead to potential iatrogenic dissemination and systemic failure. METHODS: Twenty-five patients treated for brachytherapy were recruited in the study. Controls included 4 normal men and 1 woman; case controls included 4 patients who underwent prostate biopsy for prostate cancer diagnosis. Peripheral blood (10 mL) was collected before, during, and after the brachytherapy procedure. Total RNA was isolated from mononuclear cells and phosphorus-32 RT-PCR was performed to analyze the mRNA expression of PSA and G6PDH genes. RESULTS: Of 25 patients, 23 were negative for PSA mRNA expression and 2 were positive for PSA mRNA expression before brachytherapy. Of the 23 patients who were negative for PSA mRNA expression before treatment, 15 patients (65%) turned positive during or after brachytherapy and the remaining 8 patients remained negative throughout the treatment. Eight of the 25 patients developed rising serum PSA levels. Of these 8 patients, 1 (12.5%) did not have PSA mRNA expression in the peripheral blood before, during, or after brachytherapy; the remaining 7 patients who developed rising serum PSA levels had PSA mRNA expression after brachytherapy (P = 0.03). CONCLUSIONS: These findings strongly suggest that iatrogenic shedding of prostate cells occurs as a result of brachytherapy and raises the concern that these cells liberated at the time of brachytherapy increase the risk of metastatic deposits and results in systemic failure, as measured by serum PSA levels.