SIRT6 is a pivotal regulator of lipid metabolism. It is also closely connected to cardiovascular diseases, which are the main cause of death in diabetic patients. We observed a decrease in the ...expression of SIRT6 and key autophagy effectors (ATG5, LC3B, and LAMP1) in ox‐LDL‐induced foam cells, a special form of lipid‐laden macrophages. In these cells, SIRT6 WT but not SIRT6 H133Y overexpression markedly reduced foam cell formation, as shown by Oil Red O staining, while inducing autophagy flux, as determined by both mRFP‐GFP‐LC3 labeling and transmission electron microscopy. Silencing the key autophagy initiation gene ATG5, reversed the autophagy‐promoting effect of SIRT6 in ox‐LDL‐treated THP1 cells, as evidenced by an increase in foam cells. Cholesterol efflux assays indicated that SIRT6 overexpression in foam cells promoted cholesterol efflux, increased the levels of ABCA1 and ABCG1, and reduced miR‐33 levels. By transfecting miR‐33 into cells overexpressing SIRT6, we observed that reduced foam cell formation and autophagy flux induction were largely reversed. These data imply that SIRT6 plays an essential role in protecting against atherosclerosis by reducing foam cell formation through an autophagy‐dependent pathway.
The histone deacetylase SIRT6 regulates lipid metabolism. We report that SIRT6 overexpression prevented oxidized low‐density lipoprotein (ox‐LDL)‐treated macrophages from becoming lipid‐laden macrophages called foam cells. SIRT6 overexpression induced autophagy flux in ox‐LDL‐treated macrophages, and the HDAC activity of SIRT6 was necessary for this activity. Thus, a strategy aimed at increasing SIRT6 activity could be a promising avenue for the treatment of atherosclerosis.
COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed ...very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.
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•Mice are sensitized for SARS-CoV-2 infection by Ad5-hACE2 transduction•Genetically deficient strains can be directly assessed without additional breeding•Mice useful for determining host factors necessary for optimal virus clearance•Useful for assessing efficacy of vaccines and therapies such as convalescent plasma
An adenoviral transduction-based mouse model that can be infected with SARS-CoV-2 provides a tool to understand host factors involved in viral infection and clearance as well as potential therapeutic modalities.
Cell-fate decisions remain poorly understood at the chromatin level. Here, we map chromatin remodeling dynamics during induction of pluripotent stem cells. ATAC-seq profiling of MEFs expressing ...Oct4-Sox2-Klf4 (OSK) reveals dynamic changes in chromatin states shifting from open to closed (OC) and closed to open (CO), with an initial burst of OC and an ending surge of CO. The OC loci are largely composed of genes associated with a somatic fate, while the CO loci are associated with pluripotency. Factors/conditions known to impede reprogramming prevent OSK-driven OC and skew OC-CO dynamics. While the CO loci are enriched for OSK motifs, the OC loci are not, suggesting alternative mechanisms for chromatin closing. Sap30, a Sin3A corepressor complex component, is required for the OC shift and facilitates reduced H3K27ac deposition at OC loci. These results reveal a chromatin accessibility logic during reprogramming that may apply to other cell-fate decisions.
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•ATAC-seq reveals chromatin accessibility dynamics during reprogramming•TFs associated with initial chromatin closing are barriers for reprogramming•OSK opens the pluripotent loci gradually through a direct process•OSK closes the somatic loci indirectly in part through SAP30
Li et al. show that Yamanaka factors remodel the nuclear architecture of MEFs following a binary logic that may guide further improvement in reprograming technology and be applicable for other cell-fate decisions.
Transposable elements (TEs) make up a majority of a typical eukaryote's genome, and contribute to cell heterogeneity in unclear ways. Single-cell sequencing technologies are powerful tools to explore ...cells, however analysis is typically gene-centric and TE expression has not been addressed. Here, we develop a single-cell TE processing pipeline, scTE, and report the expression of TEs in single cells in a range of biological contexts. Specific TE types are expressed in subpopulations of embryonic stem cells and are dynamically regulated during pluripotency reprogramming, differentiation, and embryogenesis. Unexpectedly, TEs are expressed in somatic cells, including human disease-specific TEs that are undetectable in bulk analyses. Finally, we apply scTE to single-cell ATAC-seq data, and demonstrate that scTE can discriminate cell type using chromatin accessibly of TEs alone. Overall, our results classify the dynamic patterns of TEs in single cells and their contributions to cell heterogeneity.
Purpose
The accurate segmentation of liver and liver tumors from CT images can assist radiologists in decision‐making and treatment planning. The contours of liver and liver tumors are currently ...obtained by manual labeling, which is time‐consuming and subjective. Computer‐aided segmentation methods have been widely used in the segmentation of liver and liver tumors. However, due to the diversity of shape, volume, and image intensity, the segmentation is still a difficult task. In this study, we present a Spatial Feature Fusion Convolutional Network (SFF‐Net) to automatically segment liver and liver tumors from CT images.
Methods
First, we extract side‐outputs at each convolutional block in SFF‐Net to make full use of multiscale features. Second, skip‐connections are added in the down‐sampling phase, therefore, the spatial information can be efficiently transferred to later layers. Third, we present feature fusion blocks (FFBs) to merge spatial features and high‐level semantic features from early layers and later layers, respectively. Finally, a fully connected 3D conditional random fields (CRFs) is applied to refine the liver and liver tumor segmentation results.
Results
We test our method on the MICCAI 2017 Liver Tumor Segmentation (LiTS) challenge dataset. The Dice Global (DG) score, Dice per case (DC) score, Volume Overlap Error (VOE), Average Symmetric Surface Distance (ASSD), and tumor precision score are calculated to evaluate the liver and liver tumor segmentation accuracies. For the liver segmentation, DG is 0.955; DC is 0.937; VOE is 0.106; and ASSD is 3.678. For the tumor segmentation, DG is 0.746; DC is 0.592; VOE is 0.416; ASSD is 1.585 and the tumor precision score is 0.369.
Conclusions
The SFF‐Net learns more spatial information by adding skip‐connections and feature fusion blocks. The experiments validate that our method can accurately segment liver and liver tumors from CT images.
Characterising the highly variable temporal dynamics of landscape-scale fire activity is best achieved using geostationary satellites, and the Himawari-8 Advanced Himawari Imager (AHI) now provides ...views of Asian and Australian fires at an unprecedented 10min temporal resolution and 2km nadir thermal channel spatial resolution. We here develop the first processing system to identify active fires and retrieve their fire radiative power (FRP) from AHI data, based on the geostationary Fire Thermal Anomaly (FTA) algorithm and FRP retrieval method originally developed for use with Meteosat SEVIRI over Africa and Europe. This scheme detects active fires covering as little as 10−3 to 10−4 of an AHI pixel, and we compare performance to the same scheme applied to data from the forerunner geostationary MTSAT imager and the FengYun-2 (FY-2) Stretched Visible and Infrared Spin Scan Radiometer (S-VISSR), and also to 1km (at nadir) polar-orbiting MODIS active fire data. We find major benefits of Himawari-8 AHI over both MTSAT and FY-2, being able to detect a substantially greater proportion of fire activity and with little impact from sensor saturation. AHI-derived FRP retrievals of detected fires show a very strong agreement and a low (3MW) bias with respect to near-simultaneous MODIS retrievals, though fires having FRP≤40MW are undercounted by AHI due to its 4× larger pixel area (at nadir) than MODIS. Large parts of Asia are characterised by smaller/lower FRP fires associated with e.g. agricultural residue burning, meaning many are at or below this AHI minimum FRP detection limit, and during June 2015 AHI fails to detect around 66% of the hotspots that MODIS detects when both sensors view the same area simultaneously. However, AHI provides 144 observation opportunities per day compared to 4 typical observations from MODIS, and shows a low (8%) active fire detection error of commission. We demonstrate the unique value of the geostationary FRP retrievals made from AHI data for full fire diurnal cycle assessment and for Fire Radiative Energy (FRE) calculations. We conclude that these FRP data demonstrate major benefits for studies of active fires over Asia and Australia, and expect them to become an important component of the global geostationary active fire observation system.
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•We developed the first fire radiative power system based on Himawari-8.•Strong agreement had been found between Himawari-8 and MODIS on a per-fire basis.•Advances in Himawari-8 system had been studied with comparison of MTSAT and FY-2.•The fire diurnal cycle and fire pattern in Asia and Australia are explored briefly.•The Himawari-8 fire system can be part of global geostationary fire system.
In recent years, conductive polymer composites have been widely studied for their electrical conductivity and electromagnetic shielding effects due to their advantages of light weight, simple ...preparation methods, and structural design versatility. In this study, oxidized multi-walled carbon nanotubes/waterborne polyurethane composites (OCNT/WPU) were prepared by grafting oxidized carbon nanotubes onto polyurethane molecular chains through in situ polymerization, using environmentally friendly waterborne polyurethane as the polymer matrix. Then, the OCNT/WPU structure was broken by high shear force, and the loading of CNTs was increased by adsorption, and a new composite structure was designed (denoted by OCWPU). The structure and morphology of OCNT/WPU and OCWPU were characterized by FT-IR and SEM. The structure and morphology of OCWPU with different multi-walled carbon nanotube loadings (CNTs/OCWPU) were characterized by SEM, Raman. Finally, the electrical conductivity and the electromagnetic shielding properties of the composites were investigated. It was found that after application of high shear force, the structure of OCWPU was disrupted and the surface activity of the material increased. With the increase in CNTs content, CNTs formed a rosette structure in the polyurethane matrix and covered the surface, and its electromagnetic shielding effect in X-bond (8.2–12.4 Ghz) would be able to reach 23 dB at 5% CNTs/OCWPU and 66.5 dB at 50% CNTs/OCWPU to meet the commercial needs. With 50% CNTs/OCWPU, an electrical conductivity of 5.1 S/cm could be achieved. This work provides a novel idea for the structural design of conductive polymer composites, which can achieve greater performance with the same carbon nanotube content.
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•Oxide-dispersion-strengthened (ODS) CoCrNi alloys with high density of coherent Y2Ti2O7 nanoprecipitates were fabricated via in situ oxidation by adding Ti and Y.•The ODS CoCrNi ...alloy with coherent Y2Ti2O7 nanoprecipitates shows an ultrahigh yield strength of 1660 MPa, 24% higher than the incoherent ODS one, while maintains the same ductility.•The ultrahigh strength of coherent ODS CoCrNi alloy is mainly attributed to the ultrafine-grained fcc matrix and the presence of coherent Y2Ti2O7 nanoprecipitates.
Oxide-dispersion-strengthened CoCrNi alloys were fabricated via in situ oxidation by adding Ti and Y, and non-in-situ oxidation by direct addition of Ti and Y2O3, referring to as Y-ODS and Y2O3-ODS alloys, respectively. Transmission electron microscopy (TEM) and atom probe tomography (APT) characterizations reveal that both alloys consist of an ultrafine-grained face-centered-cubic (fcc) matrix, a high number density of nanoscale Y-Ti-O precipitates and a small number of (Cr0.75Ti0.25)2O3 oxides. However, the nanoscale Y-Ti-O precipitates in the two alloys show distinct phase and microstructure. The Y2O3-ODS alloy contains only incoherent orthorhombic Y2TiO5 nanoprecipitates, but the Y-ODS alloy also contains a high density of fully coherent pyrochlore Y2Ti2O7 nanoprecipitates. The Y-ODS alloy achieves an ultrahigh yield strength of 1660 MPa, which is 320 MPa higher than that of the Y2O3-ODS one, but maintains the same ductility. Quantitative analysis of the strengthening mechanism indicates that such large difference in strength is mainly attributed to the presence of coherent Y2Ti2O7 nanoprecipitates in Y-ODS alloy. This study should provide significant insight into the design of ODS high/medium-entropy alloys via in situ oxidation during mechanical alloying and consolidation.
The majority of mammalian genomes are devoted to transposable elements (TEs). Whilst TEs are increasingly recognized for their important biological functions, they are a potential danger to genomic ...stability and are carefully regulated by the epigenetic system. However, the full complexity of this regulatory system is not understood. Here, using mouse embryonic stem cells, we show that TEs are suppressed by heterochromatic marks like H3K9me3, and are also labelled by all major types of chromatin modification in complex patterns, including bivalent activatory and repressive marks. We identified 29 epigenetic modifiers that significantly deregulated at least one type of TE. The loss of Setdb1, Ncor2, Rnf2, Kat5, Prmt5, Uhrf1, and Rrp8 caused widespread changes in TE expression and chromatin accessibility. These effects were context-specific, with different chromatin modifiers regulating the expression and chromatin accessibility of specific subsets of TEs. Our work reveals the complex patterns of epigenetic regulation of TEs.
The present investigation aimed to explore the neurodevelopmental trajectory of autism spectrum disorder (ASD) by identifying the changes in brain function and gene expression associated with the ...disorder. Previous studies have indicated that ASD is a highly inherited neurodevelopmental disorder of the brain that displays symptom heterogeneity across different developmental periods. However, the transcriptomic changes underlying these developmental differences remain largely unknown.
To address this gap in knowledge, our study employed resting-state functional magnetic resonance imaging (rs-fMRI) data from a large sample of male participants across four representative age groups to stratify the abnormal changes in brain function associated with ASD. Partial least square regression (PLSr) was utilized to identify unique changes in gene expression in brain regions characterized by aberrant functioning in ASD.
Our results revealed that ASD exhibits distinctive developmental trajectories in crucial brain regions such as the default mode network (DMN), temporal lobe, and prefrontal lobes during critical periods of neurodevelopment when compared to the control group. These changes were also associated with genes primarily located in synaptic tissues.
The findings of this study suggest that the neurobiology of ASD is uniquely heterogeneous across different ages and may be accompanied by distinct molecular mechanisms related to gene expression.
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