Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

Longevity is a complex phenotype influenced by both environmental and genetic factors. The genetic contribution is estimated at about 25%. Despite extensive research efforts, only a few longevity genes have been validated across populations. Long-lived individuals (LLI) reach extreme ages with a relative low prevalence of chronic disability and major age-related diseases (ARDs). We tested whether the protection from ARDs in LLI can partly be attributed to genetic factors by calculating polygenic risk scores (PRSs) for seven common late-life diseases (Alzheimer’s disease (AD), atrial fibrillation (AF), coronary artery disease (CAD), colorectal cancer (CRC), ischemic stroke (ISS), Parkinson’s disease (PD) and type 2 diabetes (T2D)). The examined sample comprised 1351 German LLI (≥94 years, including 643 centenarians) and 4680 German younger controls. For all ARD-PRSs tested, the LLI had significantly lower scores than the younger control individuals (areas under the curve (AUCs): ISS = 0.59, p = 2.84 × 10⁻³⁵; AD = 0.59, p = 3.16 × 10⁻²⁵; AF = 0.57, p = 1.07 × 10⁻¹⁶; CAD = 0.56, p = 1.88 × 10⁻¹²; CRC = 0.52, p = 5.85 × 10⁻³; PD = 0.52, p = 1.91 × 10⁻³; T2D = 0.51, p = 2.61 × 10⁻³). We combined the individual ARD-PRSs into a meta-PRS (AUC = 0.64, p = 6.45 × 10⁻¹⁵). We also generated two genome-wide polygenic scores for longevity, one with and one without the TOMM40/APOE/APOC1 gene region (AUC (incl. TOMM40/APOE/APOC1) = 0.56, p = 1.45 × 10⁻⁵, seven variants; AUC (excl. TOMM40/APOE/APOC1) = 0.55, p = 9.85 × 10⁻³, 10,361 variants). Furthermore, the inclusion of nine markers from the excluded region (not in LD with each other) plus the APOE haplotype into the model raised the AUC from 0.55 to 0.61. Thus, our results highlight the importance of TOMM40/APOE/APOC1 as a longevity hub.     

Abstracts

Journal of the American Oil Chemists' Society -     

Confinement Effects on the Structure of Entropy-Induced Supercrystals

Depletion-induced self-assembly is routinely used to separate plasmonic nanoparticles (NPs) of different shapes, but less often for its ability to create supercrystals (SCs) in suspension. Therefore, these plasmonic assemblies have not yet reached a high level of maturity and their in-depth characterization by a combination of in situ techniques is still very much needed. In this work, gold triangles (AuNTs) and silver nanorods (AgNRs) are assembled by depletion-induced self-assembly. Small Angle X-ray Scattering (SAXS) and scanning electron microscopy (SEM) analysis shows that the AuNTs and AgNRs form 3D and 2D hexagonal lattices in bulk, respectively. The colloidal crystals are also imaged by in situ Liquid-Cell Transmission Electron Microscopy. Under confinement, the affinity of the NPs for the liquid cell windows reduces their ability to stack perpendicularly to the membrane and lead to SCs with a lower dimensionality than their bulk counterparts. Moreover, extended beam irradiation leads to disassembly of the lattices, which is well described by a model accounting for the desorption kinetics highlighting the key role of the NP-membrane interaction in the structural properties of SCs in the liquid-cell. The results shed light on the reconfigurability of NP superlattices obtained by depletion-induced self-assembly, which can rearrange under confinement.     

Glucose variability in maintenance hemodialysis patients with type 2 diabetes: Comparison of dialysis and nondialysis days

Introduction

Hemodialysis (HD) induces several physiological changes that can affect plasma glucose levels in patients with diabetes and in turn their glycemic control. Studies using continuous glucose monitoring (CGM) to assess glucose variations on dialysis days compared with nondialysis days report conflicting results. Here, we used CGM to examine glucose variations induced by HD in patients with type 2 diabetes.

Methods

Patients with type 2 diabetes undergoing maintenance HD were included. CGM (Ipro2®, Medtronic) was performed at baseline and Week 4, 8, 12, and 16 for up to 7 days at each visit. CGM profiles on days where participants received HD were compared with days without HD using a linear mixed model.

Findings

Twenty-seven patients were included. The median number of CGM days performed was 8 (interquartile range [IQR] 6–10) for dialysis days and 16 (IQR 12–17) for nondialysis days. The median sensor glucose was 9.4 (95% confidence interval [CI] 8.8–10.2) mmol/L on dialysis days compared with 9.5 (95% CI 8.9–10.2) mmol/L on nondialysis days (p = 0.58). Nocturnal mean sensor glucose was higher on dialysis days compared with nondialysis days: 8.8 (95% CI 8.0–9.6) mmol/L versus 8.4 (95% CI 7.7–9.2) mmol/L (p = 0.029).

Discussion

Similar median sensor glucose values were found for days on and off HD. Nocturnal glucose levels were modestly increased on dialysis days. Our findings indicate that antidiabetic treatment does not need to be differentiated on dialysis versus nondialysis days in patients with type 2 diabetes undergoing maintenance HD.     

Adsorption to the Surface of Hemozoin Crystals: Structure-Based Design and Synthesis of Amino-Phenoxazine β-Hematin Inhibitors

In silico adsorption of eight antimalarials that inhibit β-hematin (synthetic hemozoin) formation identified a primary binding site on the (001) face, which accommodates inhibitors via formation of predominantly π-π interactions. A good correlation (r²=0.64, P=0.017) between adsorption energies and the logarithm of β-hematin inhibitory activity was found for this face. Of 53 monocyclic, bicyclic and tricyclic scaffolds, the latter yielded the most favorable adsorption energies. Five new amino-phenoxazine compounds were pursued as β-hematin inhibitors based on adsorption behaviour. The 2-substituted phenoxazines show good to moderate β-hematin inhibitory activity (<100 μM) and Plasmodium falciparum blood stage activity against the 3D7 strain. N¹,N¹-diethyl-N⁴-(10H-phenoxazin-2-yl)pentane-1,4-diamine ( P2a ) is the most promising hit with IC₅₀ values of 4.7±0.6 and 0.64±0.05 μM, respectively. Adsorption energies are predictive of β-hematin inhibitory activity, and thus the in silico approach is a beneficial tool for structure-based development of new non-quinoline inhibitors.     

An Activity-Based Nanosensor for Minimally-Invasive Measurement of Protease Activity in Traumatic Brain Injury

Current screening and diagnostic tools for traumatic brain injury (TBI) have limitations in sensitivity and prognostication. Aberrant protease activity is a central process that drives disease progression in TBI and is associated with worsened prognosis, thus direct measurements of protease activity can provide more diagnostic information. In this study, a nanosensor is engineered to release a measurable signal into the blood and urine in response to activity from the TBI-associated protease calpain. Readouts from the nanosensor are designed to be compatible with ELISA and lateral flow assays, clinically-relevant assay modalities. In a mouse model of TBI, the nanosensor sensitivity is enhanced when ligands that target hyaluronic acid are added. In evaluation of mice with mild or severe injuries, the nanosensor identifies mild TBI with a higher sensitivity than the biomarker glial fibrillary acidic protein (GFAP). This nanosensor technology allows for measurement of TBI-associated proteases without the need to directly access brain tissue and has the potential to complement existing TBI diagnostic tools.     

Solar‐grade boron emitters by BF3 plasma doping and role of the co‐implanted fluorine

We investigate the electrical properties and dopant profiles of boron emitters performed by plasma immersion ion implantation from boron trifluoride (BF₃) gas precursor, thermally annealed and passivated by silicon oxide/silicon nitride stacks. High thermal budgets are required for doses compatible with screen‐printed metal pastes, to reach very good activation rates. However, if good sheet resistances and saturation current densities may be obtained, we met strong limitations of the implied open‐circuit voltage of the n‐type Czochralski silicon substrates, which is incompatible with high‐efficiency solar cells. Such limitations are not encountered with beamline where pure B⁺ ions are implanted. Efforts on the passivation quality may improve the implied open‐circuit voltage but are not sufficient. We provide experimental comparison between beamline and plasma immersion allowing us to discriminate the causes explaining this observation (implantation technique or ion specie used) and to infer our interpretation: The co‐implantation of fluorine seems to indirectly impact the lifetime of the core substrate after thermal annealing. Copyright © 2015 John Wiley & Sons, Ltd.