The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide

The deposition and oligomerization of amyloid β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). Aβ peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by β and γ secretases. Several lines of evidence point to the soluble Aβ oligomer (AβO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the AβO species. Methodology/Principal Findings To achieve a better understanding of the mechanism of action of this disruptive ability, we extend the application of electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels in the Aβ peptide to investigate the binding and influence of fluorene compounds on AβO structure and dynamics. In addition, we have synthesized a spin-labeled fluorene (SLF) containing a pyrroline nitroxide group that provides both increased cell protection against AβO toxicity and a route to directly observe the binding of the fluorene to the AβO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block AβO toxicity, scavenge free radicals and diminish the formation of intracellular AβO species. Conclusions Fluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they posses both antioxidant properties and the ability to disrupt AβO species

Depression among Adolescents of Rural Nepal: A Community-Based Study

This community-based study is aimed at finding out the prevalence of depression, and its correlates among adolescents of rural Nepal. Data were collected among adolescents after multistage stratified proportionate random sampling by using the Patient Health Questionnaire (PHQ-9) to assess the depression among adolescent. Chi-square test and logistic regression model were applied. The prevalence of depression was found to be 27%. Adolescents who were not satisfied with their academic performance were 2.4 times more likely to have the risk of depression (AOR=2.417, CI: 1.097-5.326). Likewise, tobacco users were almost fourteen times (AOR=13.858, CI: 2.090-91.90), who intended to harm themselves were two times (AOR=2.323, CI: 1.078-5.005), sleep deprivation were fifteen folds (AOR=14.911, CI: 7.376-30.145), often scolded by their parents was almost three times (AOR=2.931, CI: 1.195-7.436), and having poor relationship with friends were 2.4 times more likely (AOR=2.371, CI: 1.078-5.215) of having depression. Sleep deprivation has a long-term negative impact on health leading depression

Perceptions towards COVID-19 Vaccines and Willingness to Vaccinate in Nepal

Vaccination is the most effective preventive measure of COVID-19 available at present, but its success depends on the global accessibility of vaccines and the willingness of people to be vaccinated. As the vaccination rollouts are increasing worldwide, it is important to assess public perception and willingness towards vaccination, so that the aim of mass vaccination will be successful. This study aimed to understand public perception towards COVID-19 vaccines and their willingness to get vaccinated in Nepal. This cross-sectional online survey was conducted among 1196 residents of Nepal in August 2021; most of the participants of this online survey were young adults (18–47 years) with university-level education. A total of 64.5% (771/1196) of the participants perceived COVID-19 vaccines to be safe and risk-free, while 68.6% (820/1196) agreed that vaccination would be efficient in the fight against this pandemic. Most of the participants (841/1196, 70.3%) disagreed that people are getting COVID-19 vaccines easily in Nepal, while they agree with the prioritization of older adults and healthcare workers for vaccination. A total of 61.1% (731/1196) of the participants had received at least one dose of the vaccine. Among the unvaccinated, 93.3% (434/465) were willing to get vaccinated when their turn came. The higher confidence of younger adults in vaccines and the vaccination process is encouraging, as that can help educate others who are hesitant or are not positive towards the idea of receiving vaccines. Dissemination of correct and current information, acquisition of enough doses of vaccines, and equitable distribution of vaccines will be required to achieve successful completion of the COVID-19 vaccination campaign in Nepal

The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide.

BackgroundThe deposition and oligomerization of amyloid β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). Aβ peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by β and γ secretases. Several lines of evidence point to the soluble Aβ oligomer (AβO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the AβO species.Methodology/principal findingsTo achieve a better understanding of the mechanism of action of this disruptive ability, we extend the application of electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels in the Aβ peptide to investigate the binding and influence of fluorene compounds on AβO structure and dynamics. In addition, we have synthesized a spin-labeled fluorene (SLF) containing a pyrroline nitroxide group that provides both increased cell protection against AβO toxicity and a route to directly observe the binding of the fluorene to the AβO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block AβO toxicity, scavenge free radicals and diminish the formation of intracellular AβO species.ConclusionsFluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they possess both antioxidant properties and the ability to disrupt AβO species

The comparison of EPR spectra from Aβ alone, an actual mixture of SLF and Aβ, and the mathematical sum of the individual EPR signals from SLF and Aβ.

<p>Data were taken for samples containing AβO spin labeled at the 2^nd residue (A) and for samples containing AβO spin labeled at the 26^th residue (B).</p

Fluorenes bind AβO and destabilize highly organized secondary structure.

<p>EPR spectra of SLF (10 µM) with single-cysteine mutant Aβ_(1–40) oligomers (40 µM) show that motional freedom of the mixture increased following a 2-hour incubation at room temperature (red) compared with 0 hours (black). A) and B) 26 AβO: spin labeled at 26^th residue C) and D) 2 AβO: spin labeled at 2^nd residue.</p

Diagram showing the locations of spin labels in Aβ_(1–40), and the structures of the HO-4160 and K01-162 fluorene compounds.

<p>Top panel:. the spin labels were targeted to either position 2 (MTS nitroxide spin label) or position 26 (TOAC nitroxide spin label) of Aβ. Position 26 lies within a putative hairpin loop connecting the terminal domains of the peptide, while position 2 is found within the N-terminal domain. Bottom panel: the structure of the SLF compound HO-4160, which is a derivative of the active fluorene K01-162 described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035443#pone.0035443-Hong1" target="_blank">[6]</a>. The core fluorene ring structure is shown in red.</p

EPR examination indicates the motional freedom of SLF is reduced by interaction with AβO.

<p>AβO imparts a broad component (arrow) into the EPR spectrum of HO-4160, reflecting a population of SLF with a slower correlation time.</p