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Augmenting traditional genome wide association studies (GWAS) with advanced machine learning algorithms can allow the detection of novel signals in available cohorts by providing complementary approaches to the existing methods. We introduce “Genome wide association neural networks (GWANN)”, a novel approach that uses neural networks (NNs) to account for nonlinear and SNP-SNP interaction effects. We applied GWANN to family history of Alzheimer’s disease (AD) in the UK Biobank. Our method identified 26 known AD genes, 2 target nominations and 67 novel genes, and validated the results against brain eQTLs, AD phenotype associations, biological pathways, disease associations and differentially expressed gene sets in the AD brain. Some drugs targeting novel GWANN hits are currently in clinical trials for AD. Applying NNs for GWAS, alongside existing methods, illustrates their potential to complement existing algorithms and methods, and enable the discovery of novel and tractable targets for AD.

Tumor Treating Fields (TTFields) are low-intensity, alternating intermediate-frequency (200 kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer over normal cells or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low- and high-grade patient glioma cell lines that TTFields ablated cilia within 24 h. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons, and multiciliated/ependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ and TTFields have opposing effects on glioma ciliogenesis. TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Surprisingly, the inhibitory effects of TTFields and TMZ on tumor cell recurrence are linked to the relative timing of TMZ exposure to TTFields and ARL13B+ cilia. Finally, TTFields disrupted cilia in patient tumors treated ex vivo. Our findings suggest that the efficacy of TTFields may depend on the degree of tumor ciliogenesis and relative timing of TMZ treatment.

Our understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid-enhanced tauopathy.We crossed an inducible tauopathy model with two β-amyloid models utilising the doxycycline-repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis and then assessed tauopathy, amyloidosis and gliosis.We combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aβ and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14-15 months and subsequently induced tau expression for 6 months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7 months before inducing expression for a subsequent 6 months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet-regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1 month before inducing expression for 5 months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy.These data suggest that tau misfolding is exacerbated by both newly forming Aβ deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of ageing, amyloid and tauopathy and to test interventions to disrupt the amyloid cascade.

We realize a single particle microscope by using deterministically extracted laser-cooled ^{40}Ca^{+} ions from a Paul trap as probe particles for transmission imaging. We demonstrate focusing of the ions to a spot size of 5.8±1.0 nm and a minimum two-sample deviation of the beam position of 1.5 nm in the focal plane. The deterministic source, even when used in combination with an imperfect detector, gives rise to a fivefold increase in the signal-to-noise ratio as compared with conventional Poissonian sources. Gating of the detector signal by the extraction event suppresses dark counts by 6 orders of magnitude. We implement a Bayes experimental design approach to microscopy in order to maximize the gain in spatial information. We demonstrate this method by determining the position of a 1 μm circular hole structure to a precision of 2.7 nm using only 579 probe particles.

Traversal of a symmetry-breaking phase transition at finite rates can lead to causally separated regions with incompatible symmetries and the formation of defects at their boundaries, which has a crucial role in quantum and statistical mechanics, cosmology and condensed matter physics. This mechanism is conjectured to follow universal scaling laws prescribed by the Kibble-Zurek mechanism. Here we determine the scaling law for defect formation in a crystal of 16 laser-cooled trapped ions, which are conducive to the precise control of structural phases and the detection of defects. The experiment reveals an exponential scaling of defect formation γ(β), where γ is the rate of traversal of the critical point and β=2.68±0.06. This supports the prediction of β=8/3≈2.67 for finite inhomogeneous systems. Our result demonstrates that the scaling laws also apply in the mesoscopic regime and emphasizes the potential for further tests of non-equilibrium thermodynamics with ion crystals.

The accurate characterization of eigenmodes and eigenfrequencies of two-dimensional ion crystals provides the foundation for the use of such structures for quantum simulation purposes. We present a combined experimental and theoretical study of two-dimensional ion crystals. We demonstrate that standard pseudopotential theory accurately predicts the positions of the ions and the location of structural transitions between different crystal configurations. However, pseudopotential theory is insufficient to determine eigenfrequencies of the two-dimensional ion crystals accurately but shows significant deviations from the experimental data obtained from resolved sideband spectroscopy. Agreement at the level of 2.5 x 10^(-3) is found with the full time-dependent Coulomb theory using the Floquet-Lyapunov approach and the effect is understood from the dynamics of two-dimensional ion crystals in the Paul trap. The results represent initial steps towards an exploitation of these structures for quantum simulation schemes., Comment: 5 pages, 4 figures, supplemental material (mathematica and matlab files) available upon request

The quest for experimental platforms that allow for the exploration, and even control, of the interplay of low dimensionality and frustration is a fundamental challenge in several fields of quantum many-body physics, such as quantum magnetism. Here, we propose the use of cold crystals of trapped ions to study a variety of frustrated quantum spin ladders. By optimizing the trap geometry, we show how to tailor the low dimensionality of the models by changing the number of legs of the ladders. Combined with a method for selectively hiding ions provided by laser addressing, it becomes possible to synthesize stripes of both triangular and Kagome lattices. Besides, the degree of frustration of the phonon-mediated spin interactions can be controlled by shaping the trap frequencies. We support our theoretical considerations by initial experiments with planar ion crystals, where a high and tunable anisotropy of the radial trap frequencies is demonstrated. We take into account an extensive list of possible error sources under typical experimental conditions, and describe explicit regimes that guarantee the validity of our scheme., publishedVersion

We report transport operations with linear crystals of 40Ca+ ions performed by applying complex electric time-dependent potentials. For their control we use the information obtained from the ions’ fluorescence. We demonstrate that by means of this feedback technique, we can transport a predefined number of ions and also split and unify ion crystals. The feedback control allows for a robust scheme, compensating for experimental errors, as it does not rely on a precisely known electrical modeling of the electric potentials in the ion trap beforehand. Our method allows us to generate a self-learning voltage ramp for the required process. With an experimental demonstration of a transport with more than 99.8% success probability, this technique may facilitate the operation of a future ion-based quantum processor.

Summary form only given.The limitations of the storage capacity of conventional optical disks may be overcome by recording the digital data holographically as microscopic reflection gratings. The data is stored bit-wise in a thin photosensitive layer coated on optical disk substrate. The pitland structure is replaced by volume gratings seated in a sub-micrometer range, which vary locally the reflectivity of the disk. For writing, a laser beam is focused within the storage layer and then reflected from the reflecting unit on the other side of the disk. The interference intensity pattern of the incident and reflected write beam induces a corresponding spatial modulation of the refractive index in a photosensitive storage medium. To retrieve the stored data, the information is reconstructed by reflection of the read beam at the induced grating.

[This corrects the article DOI: 10.1371/journal.pone.0233912.]., (Copyright: © 2023 Benjamin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)