The field of automotive user interfaces has developed rapidly over the last several years. To date, the field has primarily focused on creating user interfaces that promote safe driving, including ...when the driver is engaged in a secondary task in addition to operating the vehicle. However, researchers now need to prepare for a major change in the automotive domain: the automated driving revolution. The authors argue for a new research agenda that focuses on four challenges for automotive user interfaces: assuring safety in the age of automation, transforming vehicles into places for productivity and play, taking advantage of new mobility options made possible by automated vehicles, while throughout all this preserving user privacy and data security. This article is part of a special issue on smart vehicle spaces.
Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual ...variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10
) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10
; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10
; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10
, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.
Genomic stability is critical for the clinical use of human embryonic and induced pluripotent stem cells. We performed high-resolution SNP (single-nucleotide polymorphism) analysis on 186 pluripotent ...and 119 nonpluripotent samples. We report a higher frequency of subchromosomal copy number variations in pluripotent samples compared to nonpluripotent samples, with variations enriched in specific genomic regions. The distribution of these variations differed between hESCs and hiPSCs, characterized by large numbers of duplications found in a few hESC samples and moderate numbers of deletions distributed across many hiPSC samples. For hiPSCs, the reprogramming process was associated with deletions of tumor-suppressor genes, whereas time in culture was associated with duplications of oncogenic genes. We also observed duplications that arose during a differentiation protocol. Our results illustrate the dynamic nature of genomic abnormalities in pluripotent stem cells and the need for frequent genomic monitoring to assure phenotypic stability and clinical safety.
► hESCs and hiPSCs show more gene copy number variation than somatic cells ► Degree of abnormality differs more between hESC lines than hiPSC lines ► Deletions common in hiPSCs after reprogramming, duplications appear over time ► Recurrent duplications occur at specific genomic loci in pluripotent cells
Abstract
Structure-property relationships in ordered materials have long been a core principle in materials design. However, the introduction of disorder into materials provides structural ...flexibility and thus access to material properties that are not attainable in conventional, ordered materials. To understand disorder-property relationships, the disorder – i.e., the local ordering principles – must be quantified. Local order can be probed experimentally by diffuse scattering. The analysis is notoriously difficult, especially if only powder samples are available. Here, we combine the advantages of three-dimensional electron diffraction – a method that allows single crystal diffraction measurements on sub-micron sized crystals – and three-dimensional difference pair distribution function analysis (3D-ΔPDF) to address this problem. In this work, we compare the 3D-ΔPDF from electron diffraction data with those obtained from neutron and x-ray experiments of yttria-stabilized zirconia (Zr
0.82
Y
0.18
O
1.91
) and demonstrate the reliability of the proposed approach.
IMPORTANCE: Maternal depression and anxiety can have deleterious and lifelong consequences on child development. However, many aspects of the association of early brain development with maternal ...symptoms remain unclear. Understanding the timing of potential neurobiological alterations holds inherent value for the development and evaluation of future therapies and interventions. OBJECTIVE: To examine the association between exposure to prenatal maternal depression and anxiety symptoms and offspring white matter microstructure at 1 month of age. DESIGN, SETTING, AND PARTICIPANTS: This cohort study of 101 mother-infant dyads used a composite of depression and anxiety symptoms measured in mothers during the third trimester of pregnancy and measures of white matter microstructure characterized in the mothers’ 1-month offspring using diffusion tensor imaging and neurite orientation dispersion and density imaging performed from October 1, 2014, to November 30, 2016.Magnetic resonance imaging was performed at an academic research facility during natural, nonsedated sleep. MAIN OUTCOMES AND MEASURES: Brain mapping algorithms and statistical models were used to evaluate the association between maternal depression and anxiety and 1-month infant white matter microstructure as measured by diffusion tensor imaging and neurite orientation dispersion and density imaging findings. RESULTS: In the 101 mother-infant dyads (mean SD age of mothers, 33.22 3.99 years; mean age of infants at magnetic resonance imaging, 33.07 days range, 18-50 days; 92 white mothers 91.1%; 53 male infants 52.5%), lower 1-month white matter microstructure (decreased neurite density and increased mean, radial, and axial diffusivity) was associated in right frontal white matter microstructure with higher prenatal maternal symptoms of depression and anxiety. Significant sex × symptom interactions with measures of white matter microstructure were also observed, suggesting that white matter development may be differentially sensitive to maternal depression and anxiety symptoms in males and females during the prenatal period. CONCLUSIONS AND RELEVANCE: These data highlight the importance of the prenatal period to early brain development and suggest that the underlying white matter microstructure is associated with the continuum of prenatal maternal depression and anxiety symptoms.
Binary metal oxides are attractive anode materials for lithium-ion batteries. Despite sustained effort into nanomaterials synthesis and understanding the initial discharge mechanism, the fundamental ...chemistry underpinning the charge and subsequent cycles-thus the reversible capacity-remains poorly understood. Here, we use in operando X-ray pair distribution function analysis combining with our recently developed analytical approach employing Metropolis Monte Carlo simulations and non-negative matrix factorisation to study the charge reaction thermodynamics of a series of Fe- and Mn-oxides. As opposed to the commonly believed conversion chemistry forming rocksalt FeO and MnO, we reveal the two oxide series topotactically transform into non-native body-centred cubic FeO and zincblende MnO via displacement-like reactions whose kinetics are governed by the mobility differences between displaced species. These renewed mechanistic insights suggest avenues for the future design of metal oxide materials as well as new material synthesis routes using electrochemically-assisted methods.
The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T
17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of ...distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic T
17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα
DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic T
17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of T
17-cell-mediated autoimmune diseases.
Determining the spatial organization and morphological characteristics of molecularly defined cell types is a major bottleneck for characterizing the architecture underpinning brain function. We ...developed Expansion-Assisted Iterative Fluorescence In Situ Hybridization (EASI-FISH) to survey gene expression in brain tissue, as well as a turnkey computational pipeline to rapidly process large EASI-FISH image datasets. EASI-FISH was optimized for thick brain sections (300 μm) to facilitate reconstruction of spatio-molecular domains that generalize across brains. Using the EASI-FISH pipeline, we investigated the spatial distribution of dozens of molecularly defined cell types in the lateral hypothalamic area (LHA), a brain region with poorly defined anatomical organization. Mapping cell types in the LHA revealed nine spatially and molecularly defined subregions. EASI-FISH also facilitates iterative reanalysis of scRNA-seq datasets to determine marker-genes that further dissociated spatial and morphological heterogeneity. The EASI-FISH pipeline democratizes mapping molecularly defined cell types, enabling discoveries about brain organization.
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•EASI-FISH enables robust gene expression profiling in thick brain slices•A turnkey analysis pipeline for facile analysis of large EASI-FISH image datasets•EASI-FISH reveals molecularly defined subregions of the lateral hypothalamus•Cell type subdivisions corresponding to morphology, functional tuning, and location
Multiplexed FISH in thick tissue sections with deep-learning based 3D segmentation enables facile characterization of spatial organization for different cell types in defined brain regions.
Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that ...may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting.
► Global analysis of DNA methylation differences between somatic and pluripotent cells ► Tissue-specific DNA demethylation occurs during differentiation ► X chromosome inactivation is unstable in pluripotent cells over time in culture ► Aberrations in X inactivation and imprinting are maintained during differentiation
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