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Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.
Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.
Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.
Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
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Cells control the properties of the cytoplasm to ensure proper functioning of biochemical processes. Recent studies showed that cytoplasmic density varies in both physiological and pathological states of cells undergoing growth, division, differentiation, apoptosis, senescence, and metabolic starvation. Little is known about how cellular processes cope with these cytoplasmic variations. Here, we study how a cell cycle oscillator comprising cyclin-dependent kinase (Cdk1) responds to changes in cytoplasmic density by systematically diluting or concentrating cycling Xenopus egg extracts in cell-like microfluidic droplets. We found that the cell cycle maintains robust oscillations over a wide range of deviations from the endogenous density: as low as 0.2× to more than 1.22× relative cytoplasmic density (RCD). A further dilution or concentration from these values arrested the system in a low or high steady state of Cdk1 activity, respectively. Interestingly, diluting an arrested cytoplasm of 1.22× RCD recovers oscillations at lower than 1× RCD. Thus, the cell cycle switches reversibly between oscillatory and stable steady states at distinct thresholds depending on the direction of tuning, forming a hysteresis loop. We propose a mathematical model which recapitulates these observations and predicts that the Cdk1/Wee1/Cdc25 positive feedback loops do not contribute to the observed robustness, supported by experiments. Our system can be applied to study how cytoplasmic density affects other cellular processes.more » « less
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Abstract Multiferroic materials composed of ferromagnetic and ferroelectric components are interesting for technological applications due to sizable magnetoelectric coupling allowing the control of magnetic properties by electric fields. Due to being compatible with the silicon-based technology, HfO2-based ferroelectrics could serve as a promising component in the composite multiferroics. Recently, a strong charge-mediated magnetoelectric coupling has been predicted for a Ni/HfO2multiferroic heterostructure. Here, using density functional theory calculations, we systematically study the effects of the interfacial oxygen stoichiometry relevant to experiments on the magnetoelectric effect at the Ni/HfO2interface. We demonstrate that the magnetoelectric effect is very sensitive to the interface stoichiometry and is reversed if an oxidized Ni monolayer is formed at the interface. The reversal of the magnetoelectric effect is driven by a strong Ni−O bonding producing exchange-split polarization-sensitive antibonding states at the Fermi energy. We argue that the predicted reversal of the magnetoelectric effect is typical for other 3
d ferromagnetic metals, such as Co and Fe, where the metal-oxide antibonding states have an opposite spin polarization compared to that in the pristine ferromagnetic metals. Our results provide an important insight into the mechanism of the interfacial magnetoelectric coupling, which is essential for the physics and application of multiferroic heterostructures. -
A single-column radiative-convective model (RCM) is a useful tool to investigate the physical processes that determine the tropical tropopause layer (TTL) temperature structures. Previous studies on the TTL using the RCMs, however, omitted the cloud radiative effects. In this study, we examine the impact of cloud radiative effects on the simulated TTL temperatures using an RCM. We derive the cloud radiative effects based on satellite observations, which show heating rates in the troposphere but cooling rates in the stratosphere. We find that the cloud radiative effect warms the TTL by as much as 2 K but cools the lower stratosphere by as much as −1.5 K, resulting in a thicker TTL. With (without) considering cloud radiative effects, we obtain a convection top of ≈167 hPa (≈150 hPa) with a temperature of ≈213 K (≈209 K), and a cold point at ≈87 hPa (≈94 hPa) with a temperature of ≈204 K (≈204 K). Therefore, the cloud radiative effects widen the TTL by both lowering the convection-top height and enhancing the cold-point height. We also examine the impact of TTL cirrus radiative effects on the RCM-simulated temperatures. We find that the TTL cirrus warms the TTL with a maximum temperature increase of ≈1.3 K near 110 hPa.more » « less
