Beyond A and B Compartments: how major nuclear locales define nuclear genome organization and function.

Models of nuclear genome organization often propose a binary division into active versus inactive compartments, yet they overlook nuclear bodies. Here we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.

Coarse-to-Fine Contrastive Learning on Graphs.

Inspired by the impressive success of contrastive learning (CL), a variety of graph augmentation strategies have been employed to learn node representations in a self-supervised manner. Existing methods construct the contrastive samples by adding perturbations to the graph structure or node attributes. Although impressive results are achieved, it is rather blind to the wealth of prior information assumed: with the increase of the perturbation degree applied on the original graph: 1) the similarity between the original graph and the generated augmented graph gradually decreases and 2) the discrimination between all nodes within each augmented view gradually increases. In this article, we argue that both such prior information can be incorporated (differently) into the CL paradigm following our general ranking framework. In particular, we first interpret CL as a special case of learning to rank (L2R), which inspires us to leverage the ranking order among positive augmented views. Meanwhile, we introduce a self-ranking paradigm to ensure that the discriminative information among different nodes can be maintained and also be less altered to the perturbations of different degrees. Experiment results on various benchmark datasets verify the effectiveness of our algorithm compared with the supervised and unsupervised models.

High DC-Bias Stability and Reliability in BaTiO3-Based Multilayer Ceramic Capacitors: The Role of the Core-Shell Structure and the Electrode.

With the miniaturization of multilayer ceramic capacitors (MLCCs) and the increase of the electric field on a single dielectric layer, dielectric constant DC-bias stability and reliability have gradually aroused attention in the advanced electronics industry. In this study, MLCCs with outstanding DC-bias stability and reliability were prepared by using dielectric ceramic optimization and electrode optimization strategies. The effect of the Dy-Y doping concentration on the microstructure, dielectric properties, and reliability of BaTiO3-based ceramics was investigated. The shell ratio and effective shell doping concentration of the core-shell structure in ceramic grains play important roles in defects and electrical performances. The ceramic with appropriate doping contents shows a dielectric constant of 1800 and a dielectric constant change rate of -17% under a DC field of 4 kV/mm, which was fabricated into prototype MLCCs with different Ni electrodes. MLCCs exhibit outstanding DC-bias stability with a -28% degradation in the dielectric constant under a DC field of 4 kV/mm while possessing a dielectric constant of 2300 and satisfying the EIA X7S specification. Additionally, it was discovered that MLCCs prepared by using fine-size Ni particle electrodes have low electrode roughness and high interfacial Schottky barriers, resulting in better reliability. This study provides promising candidate materials and theoretical references for high-end and high DC-bias stability MLCCs.

Solar Thermal Textiles for On-Body Radiative Energy Collection Inspired by Polar Animals.

Humans use textiles to maintain thermal homeostasis amidst environmental extremes but known textiles have limited thermal windows. There is evidence that polar-dwelling animals have evolved a different mechanism of thermoregulation by using optical polymer materials to achieve an on-body "greenhouse" effect. Here, we design a bilayer textile to mimic these adaptations. Two ultralightweight fabrics with complementary optical functions, a polypropylene visible-transparent insulator and a nylon visible-absorber-infrared-reflector coated with a conjugated polymer, perform the same putative function as polar bear hair and skin, respectively. While retaining familiar textile qualities, these layers suppress dissipation of body heat and maximize radiative absorption of visible light. Under moderate illumination of 130 W/m2, the textile achieves a heating effect of +10 °C relative to a typical cotton T-shirt which is 30% heavier. Current approaches to personal radiative heating are limited to absorber/reflector layer optimization alone and fail to reproduce the thermoregulation afforded by the absorber-transmitter structure of polar animal pelts. With increasing pressures to adapt to a rapidly changing climate, our work leverages optical polymers to bridge this gap and evolve the basic function of textiles.

Effects of Oat ß-Glucan on the Textural and Sensory Properties of Low-Fat Set Type Pea Protein Yogurt.

This study investigated the effect of oat ß-glucan as a fat substitute on the structure formation, texture, and sensory properties of pea protein yogurt. The results showed that the incorporation of 0.5% ß-glucan significantly accelerated the lactic acid bacteria-induced fermentation, with the time for reaching the target pH of 4.6 shortened from 3.5 h to 3 h (p < 0.05); increased the plastic module (G') from 693 Pa to 764 Pa when fermenting 3 h (p < 0.05); and enhanced the water-holding capacity from 77.29% to 82.15% (p < 0.05). The identification of volatile organic compounds (VOCs) in low-fat pea protein yogurt by GC-IMS revealed a significant decrease in aldehydes and a significant increase in alcohols, ketones and acids in the pea yogurt after fermentation (p < 0.05). Among them, the levels of acetic acid, acetone, 2,3-butanedione, 3-hydroxy-2-butanone, and ethyl acetate all significantly increased with the addition of oat ß-glucan (p < 0.05), thereby providing prominent fruity, sweet, and creamy flavors, respectively. Combined with the results of sensory analysis, the quality characteristics of pea protein yogurt with 1% oil by adding 1% oat ß-glucan were comparable to the control sample with 3% oil. Therefore, oat ß-glucan has a good potential for fat replacement in pea protein yogurt.

Colorimetric Cotton Swab for Viral Protease Detection.

Reporting the activity of a specific viral protease remains an acute need for rapid point-of-care detection strategies that can distinguish active infection from a resolved infection. In this work, we present a simple colorimetric approach for reporting the activity of a specific viral protease through direct color conversion on a cotton swab, which has the potential to be extended to detect the corresponding virus. We use SARS-CoV-2 viral protease as a proof-of-concept model system. We use 4-aminomalachite green (4-AMG) as the base chromophore structure to design a CoV2-AMG reporter, which is selective toward the SARS-CoV-2 Mpro but does not produce any observable color change in the presence of other viral proteases. The color change is observable by the naked eye, as well as smartphone imaging, which affords a lower limit of detection. The simplicity and generalizability of the method could be instrumental in combating future viral outbreaks.

Cohesin-mediated loop anchors confine the locations of human replication origins.

DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)3-6, subTADs7 and loops8 in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.

Modeling zero inflation is not necessary for spatial transcriptomics.

BACKGROUND: Spatial transcriptomics are a set of new technologies that profile gene expression on tissues with spatial localization information. With technological advances, recent spatial transcriptomics data are often in the form of sparse counts with an excessive amount of zero values. RESULTS: We perform a comprehensive analysis on 20 spatial transcriptomics datasets collected from 11 distinct technologies to characterize the distributional properties of the expression count data and understand the statistical nature of the zero values. Across datasets, we show that a substantial fraction of genes displays overdispersion and/or zero inflation that cannot be accounted for by a Poisson model, with genes displaying overdispersion substantially overlapped with genes displaying zero inflation. In addition, we find that either the Poisson or the negative binomial model is sufficient for modeling the majority of genes across most spatial transcriptomics technologies. We further show major sources of overdispersion and zero inflation in spatial transcriptomics including gene expression heterogeneity across tissue locations and spatial distribution of cell types. In particular, when we focus on a relatively homogeneous set of tissue locations or control for cell type compositions, the number of detected overdispersed and/or zero-inflated genes is substantially reduced, and a simple Poisson model is often sufficient to fit the gene expression data there. CONCLUSIONS: Our study provides the first comprehensive evidence that excessive zeros in spatial transcriptomics are not due to zero inflation, supporting the use of count models without a zero inflation component for modeling spatial transcriptomics.

Rare variants and the oligogenic architecture of autism.

Most large-scale genetic studies of autism have focused on the discovery of genes by proving an enrichment of de novo mutations (DNMs) in autism probands or characterizing polygenic risk based on the association of common variants. We present evidence in support of an oligogenic model where two or more ultrarare mutations of more modest effect are preferentially transmitted to children with autism. Such private gene-disruptive mutations are enriched in families where there are multiple affected individuals, emerged two or three generations ago, and map to genes not previously associated with autism. Although no single gene has reached statistical significance, this class of variation should be considered along with genetic and nongenetic factors to better explain the etiology of this complex trait.

Replication timing maintains the global epigenetic state in human cells.

The temporal order of DNA replication [replication timing (RT)] is correlated with chromatin modifications and three-dimensional genome architecture; however, causal links have not been established, largely because of an inability to manipulate the global RT program. We show that loss of RIF1 causes near-complete elimination of the RT program by increasing heterogeneity between individual cells. RT changes are coupled with widespread alterations in chromatin modifications and genome compartmentalization. Conditional depletion of RIF1 causes replication-dependent disruption of histone modifications and alterations in genome architecture. These effects were magnified with successive cycles of altered RT. These results support models in which the timing of chromatin replication and thus assembly plays a key role in maintaining the global epigenetic state.

Intelligent Health Care: Applications of Deep Learning in Computational Medicine.

With the progress of medical technology, biomedical field ushered in the era of big data, based on which and driven by artificial intelligence technology, computational medicine has emerged. People need to extract the effective information contained in these big biomedical data to promote the development of precision medicine. Traditionally, the machine learning methods are used to dig out biomedical data to find the features from data, which generally rely on feature engineering and domain knowledge of experts, requiring tremendous time and human resources. Different from traditional approaches, deep learning, as a cutting-edge machine learning branch, can automatically learn complex and robust feature from raw data without the need for feature engineering. The applications of deep learning in medical image, electronic health record, genomics, and drug development are studied, where the suggestion is that deep learning has obvious advantage in making full use of biomedical data and improving medical health level. Deep learning plays an increasingly important role in the field of medical health and has a broad prospect of application. However, the problems and challenges of deep learning in computational medical health still exist, including insufficient data, interpretability, data privacy, and heterogeneity. Analysis and discussion on these problems provide a reference to improve the application of deep learning in medical health.

Polarised maintenance of cytoophidia in Drosophila follicle epithelia.

The metabolic enzyme CTP synthase (CTPS) can form filamentous structures named cytoophidia in numerous types of cells, including follicle cells. However, the regulation of cytoophidium assembly remains elusive. The apicobasal polarity, a defining characteristic of Drosophila follicle epithelium, is established and regulated by a variety of membrane domains. Here we show that CTPS can form cytoophidia in Drosophila epithelial follicle cells. Cytoophidia localise to the basolateral side of follicle cells. If apical polarity regulators are knocked down, cytoophidia become unstable and distribute abnormally. Knockdown of basolateral polarity regulators has no significant effect on cytoophidia, even though the polarity is disturbed. Our results indicate that cytoophidia are maintained via polarised distribution on the basolateral side of Drosophila follicle epithelia, which is primarily achieved through the apical polarity regulators.

STATISTICAL COMPARISONS OF CHROMOSOMAL SHAPE POPULATIONS.

This paper develops statistical tools for testing differences in shapes of chromosomes resulting from certain gene knockouts (KO), specifically RIF1 gene KO (RKO) and the cohesin subunit RAD21 gene KO (CKO). It utilizes a two-sample test for comparing shapes of KO chromosomes with wild type (WT) at two levels: (1) Coarse shape analysis, where one compares shapes of full or large parts of chromosomes, and (2) Fine shape analysis, where chromosomes are first segmented into (TAD-based) pieces and then the corresponding pieces are compared across populations. The shape comparisons - coarse and fine - are based on an elastic shape metric for comparing shapes of 3D curves. The experiments show that the KO populations, RKO and CKO, have statistically significant differences from WT at both coarse and fine levels. Furthermore, this framework highlights local regions where these differences are most prominent.

Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI.

BACKGROUND: AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown. METHODS: In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI. RESULTS: Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups. CONCLUSIONS: Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.

Modulated Sn Oxidation States over a Cu2O-Derived Substrate for Selective Electrochemical CO2 Reduction.

Pursuing high catalytic selectivity is challenging but paramount for an efficient and low-cost CO2 electrochemical reduction (CO2R). In this work, we demonstrate a significant correlation between the selectivity of CO2R to formate and the duration of tin (Sn) electrodeposition over a cuprous oxide (Cu2O)-derived substrate. A Sn electrodeposition time of 120 s led to a cathode with a formate Faradaic efficiency of around 81% at -1.1 V vs reversible hydrogen electrode (RHE), which was more than 37% higher than those of the Sn foil and the sample treated for 684 s. This result highlights the significant role of the interface between deposited Sn and the cuprous-derived substrate in determining the selectivity of CO2R. High-resolution X-ray photoelectron spectra revealed that the residual cuprous species at the Cu/Sn interfaces could stabilize Sn species in oxidation states of 2+ and 4+, a mixture of which is essential for a selective formate conversion. Such modulation effects likely arise from the moderate electronegativity of the cuprous species that is lower than that of Sn2+ but higher than that of Sn4+. Our work highlights the significant role of the substrate in the selectivity of the deposited catalyst and provides a new avenue to advance selective electrodes for CO2 electrochemical reduction.

High-resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells.

BACKGROUND: DNA replication in mammalian cells occurs in a defined temporal order during S phase, known as the replication timing (RT) programme. Replication timing is developmentally regulated and correlated with chromatin conformation and local transcriptional potential. Here, we present RT profiles of unprecedented temporal resolution in two human embryonic stem cell lines, human colon carcinoma line HCT116, and mouse embryonic stem cells and their neural progenitor derivatives. RESULTS: Fine temporal windows revealed a remarkable degree of cell-to-cell conservation in RT, particularly at the very beginning and ends of S phase, and identified 5 temporal patterns of replication in all cell types, consistent with varying degrees of initiation efficiency. Zones of replication initiation (IZs) were detected throughout S phase and interacted in 3D space preferentially with other IZs of similar firing time. Temporal transition regions were resolved into segments of uni-directional replication punctuated at specific sites by small, inefficient IZs. Sites of convergent replication were divided into sites of termination or large constant timing regions consisting of many synchronous IZs in tandem. Developmental transitions in RT occured mainly by activating or inactivating individual IZs or occasionally by altering IZ firing time, demonstrating that IZs, rather than individual origins, are the units of developmental regulation. Finally, haplotype phasing revealed numerous regions of allele-specific and allele-independent asynchronous replication. Allele-independent asynchronous replication was correlated with the presence of previously mapped common fragile sites. CONCLUSIONS: Altogether, these data provide a detailed temporal choreography of DNA replication in mammalian cells.

Local rewiring of genome-nuclear lamina interactions by transcription.

Transcriptionally inactive genes are often positioned at the nuclear lamina (NL), as part of large lamina-associated domains (LADs). Activation of such genes is often accompanied by repositioning toward the nuclear interior. How this process works and how it impacts flanking chromosomal regions are poorly understood. We addressed these questions by systematic activation or inactivation of individual genes, followed by detailed genome-wide analysis of NL interactions, replication timing, and transcription patterns. Gene activation inside LADs typically causes NL detachment of the entire transcription unit, but rarely more than 50-100 kb of flanking DNA, even when multiple neighboring genes are activated. The degree of detachment depends on the expression level and the length of the activated gene. Loss of NL interactions coincides with a switch from late to early replication timing, but the latter can involve longer stretches of DNA. Inactivation of active genes can lead to increased NL contacts. These extensive datasets are a resource for the analysis of LAD rewiring by transcription and reveal a remarkable flexibility of interphase chromosomes.

Rapid Irreversible Transcriptional Reprogramming in Human Stem Cells Accompanied by Discordance between Replication Timing and Chromatin Compartment.

The temporal order of DNA replication is regulated during development and is highly correlated with gene expression, histone modifications and 3D genome architecture. We tracked changes in replication timing, gene expression, and chromatin conformation capture (Hi-C) A/B compartments over the first two cell cycles during differentiation of human embryonic stem cells to definitive endoderm. Remarkably, transcriptional programs were irreversibly reprogrammed within the first cell cycle and were largely but not universally coordinated with replication timing changes. Moreover, changes in A/B compartment and several histone modifications that normally correlate strongly with replication timing showed weak correlation during the early cell cycles of differentiation but showed increased alignment in later differentiation stages and in terminally differentiated cell lines. Thus, epigenetic cell fate transitions during early differentiation can occur despite dynamic and discordant changes in otherwise highly correlated genomic properties.

Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.

The temporal order of DNA replication (replication timing [RT]) is highly coupled with genome architecture, but cis-elements regulating either remain elusive. We created a series of CRISPR-mediated deletions and inversions of a pluripotency-associated topologically associating domain (TAD) in mouse ESCs. CTCF-associated domain boundaries were dispensable for RT. CTCF protein depletion weakened most TAD boundaries but had no effect on RT or A/B compartmentalization genome-wide. By contrast, deletion of three intra-TAD CTCF-independent 3D contact sites caused a domain-wide early-to-late RT shift, an A-to-B compartment switch, weakening of TAD architecture, and loss of transcription. The dispensability of TAD boundaries and the necessity of these "early replication control elements" (ERCEs) was validated by deletions and inversions at additional domains. Our results demonstrate that discrete cis-regulatory elements orchestrate domain-wide RT, A/B compartmentalization, TAD architecture, and transcription, revealing fundamental principles linking genome structure and function.

Replication Domains: Genome Compartmentalization into Functional Replication Units.

DNA replication occurs in a defined temporal order during S phase, known as the replication timing programme, which is regulated not only during the cell cycle but also during the process of development and differentiation. The units of replication timing regulation, known as replication domains (RDs), frequently comprise several nearly synchronously firing replication origins. Replication domains correspond to topologically associating domains (TADs) mapped by chromatin conformation capture methods and are likely to be the molecular equivalents of replication foci observed using cytogenetic methods. Both TAD and replication foci are considered to be stable structural units of chromosomes, conserved through the cell cycle and development, and accordingly, the boundaries of RDs also appear to be stable in different cell types. During both normal development and progression of disease, distinct cell states are characterized by unique replication timing signatures, with approximately half of genomic RDs switching replication timing between these cell states. Advances in functional genomics provide hope that we can soon gain an understanding of the cause and consequence of the replication timing programme and its myriad correlations with chromatin context and gene regulation.