Notes

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cognitive decline in older adults at risk of dementia. By establishing the efficacy of multidomain interventions in preventing cognitive decline, SINGER aims to implement the findings into public health and clinical practices by informing policy makers, and guiding the design of community- and individual-level health promotion initiatives.
SINGER is part of the Worldwide-FINGERS international network, which is at the forefront of harmonizing approaches to effective non-pharmacological interventions in delaying cognitive decline in older adults at risk of dementia. By establishing the efficacy of multidomain interventions in preventing cognitive decline, SINGER aims to implement the findings into public health and clinical practices by informing policy makers, and guiding the design of community- and individual-level health promotion initiatives.
Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear.

To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD.

MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-relatedadherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. learn more Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date NCT04063124 (08/21/2019).
Reliable, widely accessible and affordable biomarkers for predicting Alzheimer's disease (AD) brain pathology status are a necessity to aid development of prevention strategies in cognitively healthy at-risk older adults, at the right timepoint. Measurements of the key neuropathological hallmark beta-amyloid (Aβ) by PET neuroimaging or cerebrospinal fluid measures reflect its accumulation in the brain, yet recent methodological advancements now enable blood-based measures reflecting cerebral amyloid burden.

The current study validated the capacity of plasma Aβ42/Aβ40 measured using six different assays to predict amyloid positivity in a subgroup of cognitively unimpaired (CU) participants in the ADNI study and assessed its ability to discriminate CU from AD cases. We also explored economic viability of using two different plasma amyloid assays for pre-screening in AD prevention trials and as routine clinical diagnostic tool, versus amyloid PET alone.

A cross-sectional analysis of plasma and brain amyloifew available treatment strategies, dementia prevention is a global priority. CU individuals at risk for AD are the target population for dementia prevention but have been poorly studied. Our findings confirming diagnostic value of ultrasensitive immunoassays and high-performance immunoprecipitation coupled with MS for measurement of plasma Aβ42/Aβ40 to detect PET amyloid positivity in CU participants allude to potential clinical utility of this biomarker. Plasma Aβ42/Aβ40 could be optimal for pre-selecting at-risk candidates for more invasive and expensive investigations across AD prevention clinical trials and clinical care for a rapidly ageing population.Since developing an effective treatment for Alzheimer's disease (AD) has been encountered as a challenging task, attempts to prevent cognitive decline by lifestyle modifications have become increasingly appealing. Physical exercise, healthy diet, and cognitive training are all modifiable, non-pharmacological lifestyle factors considered to influence cognitive health. Implementing lifestyle modifications on animal models of AD and cognitive impairment may reveal underlying mechanisms of action by which healthy lifestyle contribute to brain health. In mice, different types of lifestyle interventions have been shown to improve cognitive abilities, alleviate AD-related pathology and neuroinflammation, restore mitochondrial function, and have a positive impact on neurogenesis and cell survival. Different proteins and pathways have been identified to mediate some of the responses, amongst them BDNF, Akt-GSK3β, JNK, and ROCK pathway. Although some important pathways have been identified as mediating improvements in brain health, more research is needed to confirm these mechanisms of action and to improve the understanding of their interplay. Moreover, multidomain lifestyle interventions targeting multiple risk factors simultaneously may be a promising avenue in future dementia prevention strategies. Therefore, future work is needed to better understand the synergistic impact of combinatory lifestyle strategies on cellular mechanisms and brain health.Mimusops coriacea (A. DC.) Miq. (Sapotoideae, Sapotaceae, Ericales) is native to Madagascar and the Comoro Islands. This species is cultivated in many countries around the world and grows on sand in coastal vegetation. Here we sequenced, assembled, and annotated the first complete chloroplast genome of M. coriacea. The newly assembled chloroplast was analyzed with other available chloroplasts of Sapotaceae. Our results found a general conserved structure. The complete chloroplast genome has 159,689 bp, including 133 genes distributed in four regions a large single-copy region of 88,887 bp, a small single-copy region of 18,618 bp, and two inverted repeats of 26,092 bp each. Our maximum likelihood phylogenetic tree was generated with 80 protein-coding genes and recovered a monophyletic Sapotaceae sister to a clade formed by Ebenaceae + Primulaceae. In our analysis, Mimusops coriacea clustered with the other eight species of Sapotaceae included in the study.Lycosa is one of the most speciose genera in Lycosidae, including species with different sexual chromosome systems (SCS). We carried out cytogenetic analyses in three species of Lycosa, revealing that L. erythrognatha and L. sericovittata share 2n ♂ = 22 and SCS X1X20 while L. gr. nordenskjoldi presents 2n ♂ = 19 and SCS XO, composed only of acrocentric chromosomes. All species shared pericentromeric heterochromatin. Nonetheless, one specimen of L. sericovittata carried two chromosomes with terminal heterochromatin and L. gr. nordenskjoldi showed four chromosomes with interstitial heterochromatin plus another chromosome with terminal C-bands. The pericentromeric heterochromatin of all species as well as the terminal heterochromatic blocks in L. sericovittata were CMA3+. The 18S rDNA sites varied in number and type of bearing chromosomes both at inter and intrapopulational levels, with the highest variation in L. gr. nordenskjoldi. These differences may be related to gene dispersal due to the influence of transposition elements and translocation events. Despite these variations, all species shared ribosomal sites in pair 5. This study demonstrated intra and interspecific chromosomal variability of Lycosa, suggesting that chromosomal rearrangements are related to the diversification of diploid number and SCS in this group of spiders.Nanobubbles at solid-liquid interfaces play a key role in various physicochemical phenomena and it is crucial to understand their unique properties. However, little is known about their interfacial tensions due to the lack of reliable calculation methods. Based on mechanical and thermodynamic insights, we quantified for the first time the liquid-gas, solid-liquid, and solid-gas interfacial tensions of submicron-sized nitrogen bubbles at graphite-water interfaces using molecular dynamics (MD) analysis. It was revealed that Young's equation holds even for nanobubbles with different radii. We found that the liquid-gas and solid-liquid interfacial tensions were not largely affected by the gas density inside the nanobubbles. In contrast, the size effect on the solid-gas interfacial tension was observed, namely, the value dramatically decreased upon an increase in the gas density due to gas adsorption on the solid surface. However, our quantitative evaluation also revealed that the gas density effect on the contact angles is negligible when the footprint radius is larger than 50 nm, which is a typical range observed in experiments, and thus the flat shape and stabilization of submicron-sized surface bubbles observed in experiments cannot be explained only by the changes in interfacial tensions due to the van der Waals interaction-induced gas adsorption, namely by Young's equation without introducing the pinning effect. Based on our analysis, it was clarified that additional factors such as the differences in the studied systems are needed to explain the unresolved open issues - a satisfactory explanation for the nanobubbles in MD simulations being ultradense, non-flat, and stable without pinning.We have unveiled an efficient synthesis of cyanoalkylated quinoxalin-2(1H)-ones via a three-component radical cascade reaction of quinoxalin-2(1H)-ones with vinylarenes and azobis(alkylcarbonitrile)s. K2S2O8 takes part in the reaction as a sole oxidant under base, additive, and metal-free conditions, producing the three-component products in moderate to good yields. The protocol also works with phenylacetylene in the absence of vinyl arenes and provides the respective product. Furthermore, different control experiments with radical scavengers like 2,2,6,6-tetramethylpiperidine-1-oxyl and diphenyl ethylene prove the generation of radicals during the reaction.
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