iSMOD: an integrative browser for image-based single-cell multi-omics data.

Genomic and transcriptomic image data, represented by DNA and RNA fluorescence in situ hybridization (FISH), respectively, together with proteomic data, particularly that related to nuclear proteins, can help elucidate gene regulation in relation to the spatial positions of chromatins, messenger RNAs, and key proteins. However, methods for image-based multi-omics data collection and analysis are lacking. To this end, we aimed to develop the first integrative browser called iSMOD (image-based Single-cell Multi-omics Database) to collect and browse comprehensive FISH and nucleus proteomics data based on the title, abstract, and related experimental figures, which integrates multi-omics studies focusing on the key players in the cell nucleus from 20 000+ (still growing) published papers. We have also provided several exemplar demonstrations to show iSMOD's wide applications-profiling multi-omics research to reveal the molecular target for diseases; exploring the working mechanism behind biological phenomena using multi-omics interactions, and integrating the 3D multi-omics data in a virtual cell nucleus. iSMOD is a cornerstone for delineating a global view of relevant research to enable the integration of scattered data and thus provides new insights regarding the missing components of molecular pathway mechanisms and facilitates improved and efficient scientific research.

The loss of heterochromatin is associated with multiscale three-dimensional genome reorganization and aberrant transcription during cellular senescence.

Heterochromatin remodeling is critical for various cell processes. In particular, the "loss of heterochromatin" phenotype in cellular senescence is associated with the process of aging and age-related disorders. Although biological processes of senescent cells, including senescence-associated heterochromatin foci (SAHF) formation, chromosome compaction, and redistribution of key proteins, have been closely associated with high-order chromatin structure, the relationship between the high-order chromatin reorganization and the loss of heterochromatin phenotype during senescence has not been fully understood. By using senescent and deep senescent fibroblasts induced by DNA damage harboring the "loss of heterochromatin" phenotype, we observed progressive 3D reorganization of heterochromatin during senescence. Facultative and constitutive heterochromatin marked by H3K27me3 and H3K9me3, respectively, show different alterations. Facultative heterochromatin tends to switch from the repressive B-compartment to the active A-compartment, whereas constitutive heterochromatin shows no significant changes at the compartment level but enhanced interactions between themselves. Both types of heterochromatin show increased chromatin accessibility and gene expression leakage during senescence. Furthermore, increased chromatin accessibility in potential CTCF binding sites accompanies the establishment of novel loops in constitutive heterochromatin. Finally, we also observed aberrant expression of repetitive elements, including LTR (long terminal repeat) and satellite classes. Overall, facultative and constitutive heterochromatin show both similar and distinct multiscale alterations in the 3D map, chromatin accessibility, and gene expression leakage. This study provides an epigenomic map of heterochromatin reorganization during senescence.

Single-cell and spatial transcriptome analyses revealed cell heterogeneity and immune environment alternations in metastatic axillary lymph nodes in breast cancer.

BACKGROUND: Tumor heterogeneity plays essential roles in developing cancer therapies, including therapies for breast cancer (BC). In addition, it is also very important to understand the relationships between tumor microenvironments and the systematic immune environment. METHODS: Here, we performed single-cell, VDJ sequencing and spatial transcriptome analyses on tumor and adjacent normal tissue as well as axillar lymph nodes (LNs) and peripheral blood mononuclear cells (PBMCs) from 8 BC patients. RESULTS: We found that myeloid cells exhibited environment-dependent plasticity, where a group of macrophages with both M1 and M2 signatures possessed high tumor specificity spatially and was associated with worse patient survival. Cytotoxic T cells in tumor sites evolved in a separate path from those in the circulatory system. T cell receptor (TCR) repertoires in metastatic LNs showed significant higher consistency with TCRs in tumor than those in nonmetastatic LNs and PBMCs, suggesting the existence of common neo-antigens across metastatic LNs and primary tumor cites. In addition, the immune environment in metastatic LNs had transformed into a tumor-like status, where pro-inflammatory macrophages and exhausted T cells were upregulated, accompanied by a decrease in B cells and neutrophils. Finally, cell interactions showed that cancer-associated fibroblasts (CAFs) contributed most to shaping the immune-suppressive microenvironment, while CD8+ cells were the most signal-responsive cells. CONCLUSIONS: This study revealed the cell structures of both micro- and macroenvironments, revealed how different cells diverged in related contexts as well as their prognostic capacities, and displayed a landscape of cell interactions with spatial information.

Allelic reprogramming of 3D chromatin architecture during early mammalian development.

In mammals, chromatin organization undergoes drastic reprogramming after fertilization. However, the three-dimensional structure of chromatin and its reprogramming in preimplantation development remain poorly understood. Here, by developing a low-input Hi-C (genome-wide chromosome conformation capture) approach, we examined the reprogramming of chromatin organization during early development in mice. We found that oocytes in metaphase II show homogeneous chromatin folding that lacks detectable topologically associating domains (TADs) and chromatin compartments. Strikingly, chromatin shows greatly diminished higher-order structure after fertilization. Unexpectedly, the subsequent establishment of chromatin organization is a prolonged process that extends through preimplantation development, as characterized by slow consolidation of TADs and segregation of chromatin compartments. The two sets of parental chromosomes are spatially separated from each other and display distinct compartmentalization in zygotes. Such allele separation and allelic compartmentalization can be found as late as the 8-cell stage. Finally, we show that chromatin compaction in preimplantation embryos can partially proceed in the absence of zygotic transcription and is a multi-level hierarchical process. Taken together, our data suggest that chromatin may exist in a markedly relaxed state after fertilization, followed by progressive maturation of higher-order chromatin architecture during early development.

1-Tetradecanol, Diethyl Phthalate and Tween 80 Assist in the Formation of Thermo-Responsive Azoxystrobin Nanoparticles.

The occurrence of crop fungal diseases is closely related to warm environmental conditions. In order to control the release of fungicides in response to warm conditions, and enhance the efficacy, a series of thermo-responsive fungicide-loaded nanoparticles were developed. The fungicide azoxystrobin, solvent DEP, emulsifier Tween 80 and thermo-responsive component TDA were combined to create thermal-response oil phases, conditions for emulsification were then optimized. LDLS, zeta potential, FTIR, DSC, TGA, XRD, SEM and antifungal efficacy assays were carried out to investigate the characteristics and forming mechanism. The results indicated that the formula with 5 g azoxystrobin, 10 mL DEP, 6 mL Tween 80 and 2.5 g TDA constructed the proposed oil phase with the ability to transform from solid at 20 °C to softerned at 31.5 °C. Both DEP and TDA played key roles in interfering with the crystallization of azoxystrobin. The optimal T3t-c12 nanoparticles had a mean particle size of 162.1 nm, thermo-responsive morphological transformation between 20 °C and 30 °C, AZO crystal reforming after drying, the ability to attach to fungal spores and satisfied antifungal efficacy against P. nicotiana PNgz07 and A. niger A1513 at 30 °C. This report provides referable technical support for the construction of smart-release nanoparticles of other agrochemicals.

Molecular basis for histone H3 "K4me3-K9me3/2" methylation pattern readout by Spindlin1.

Histone recognition by "reader" modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as "K4me3-R8me2a" and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 "K4me3-K9me3/2" bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 "K4me3-K9me3" peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 "K4me3-K9me3/2" bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.

Web3DMol: interactive protein structure visualization based on WebGL.

A growing number of web-based databases and tools for protein research are being developed. There is now a widespread need for visualization tools to present the three-dimensional (3D) structure of proteins in web browsers. Here, we introduce our 3D modeling program-Web3DMol-a web application focusing on protein structure visualization in modern web browsers. Users submit a PDB identification code or select a PDB archive from their local disk, and Web3DMol will display and allow interactive manipulation of the 3D structure. Featured functions, such as sequence plot, fragment segmentation, measure tool and meta-information display, are offered for users to gain a better understanding of protein structure. Easy-to-use APIs are available for developers to reuse and extend Web3DMol. Web3DMol can be freely accessed at http://web3dmol.duapp.com/, and the source code is distributed under the MIT license.

Developing novel methods to image and visualize 3D genomes.

To investigate three-dimensional (3D) genome organization in prokaryotic and eukaryotic cells, three main strategies are employed, namely nuclear proximity ligation-based methods, imaging tools (such as fluorescence in situ hybridization (FISH) and its derivatives), and computational/visualization methods. Proximity ligation-based methods are based on digestion and re-ligation of physically proximal cross-linked chromatin fragments accompanied by massively parallel DNA sequencing to measure the relative spatial proximity between genomic loci. Imaging tools enable direct visualization and quantification of spatial distances between genomic loci, and advanced implementation of (super-resolution) microscopy helps to significantly improve the resolution of images. Computational methods are used to map global 3D genome structures at various scales driven by experimental data, and visualization methods are used to visualize genome 3D structures in virtual 3D space-based on algorithms. In this review, we focus on the introduction of novel imaging and visualization methods to study 3D genomes. First, we introduce the progress made recently in 3D genome imaging in both fixed cell and live cells based on long-probe labeling, short-probe labeling, RNA FISH, and the CRISPR system. As the fluorescence-capturing capability of a particular microscope is very important for the sensitivity of bioimaging experiments, we also introduce two novel super-resolution microscopy methods, SDOM and low-power super-resolution STED, which have potential for time-lapse super-resolution live-cell imaging of chromatin. Finally, we review some software tools developed recently to visualize proximity ligation-based data. The imaging and visualization methods are complementary to each other, and all three strategies are not mutually exclusive. These methods provide powerful tools to explore the mechanisms of gene regulation and transcription in cell nuclei.

Centlein, a novel microtubule-associated protein stabilizing microtubules and involved in neurite formation.

We have previously reported that the centriolar protein centlein functions as a molecular link between C-Nap1 and Cep68 to maintain centrosome cohesion [1]. In this study, we identified centlein as a novel microtubule-associated protein (MAP), directly binding to purified microtubules (MTs) via its longest coiled-coil domain. Overexpression of centlein caused profound nocodazole- and cold-resistant MT bundles, which also relied on its MT-binding domain. siRNA-mediated centlein depletion resulted in a significant reduction in tubulin acetylation level and overall fluorescence intensity of cytoplasmic MT acetylation. Centlein was further characterized in neurons. We found that centlein overexpression inhibited neurite formation in retinoic acid (RA)-induced SH-SY5Y and N2a cells. Taken together, we propose that centlein is involved in MT stability and neuritogenesis in vivo.

Modular coherence of protein dynamics in yeast cell polarity system.

In this study, we investigated on a systems level how complex protein interactions underlying cell polarity in yeast determine the dynamic association of proteins with the polar cortical domain (PCD) where they localize and perform morphogenetic functions. We constructed a network of physical interactions among >100 proteins localized to the PCD. This network was further divided into five robust modules correlating with distinct subprocesses associated with cell polarity. Based on this reconstructed network, we proposed a simple model that approximates a PCD protein's molecular residence time as the sum of the characteristic time constants of the functional modules with which it interacts, weighted by the number of edges forming these interactions. Regression analyses showed excellent fitting of the model with experimentally measured residence times for a large subset of the PCD proteins. The model is able to predict residence times using small training sets. Our analysis also revealed a scaffold protein that imposes a local constraint of dynamics for certain interacting proteins.

Whole-genome sequence of Pseudomonas benzopyrenica MLY92: isolation from diseased leaves of tobacco in China.

Here we present a sketch of the whole-genome sequence of Pseudomonas benzopyrenica. The strain comes from the leaf veins of a diseased tobacco plant. This study has significant research implications for gaining insights into the characteristics of microorganisms belonging to the genus Pseudomonas.

Molecular Basis for SPINDOC-Spindlin1 Engagement and Its Role in Transcriptional Attenuation.

Spindlin1 is a histone reader with three Tudor-like domains and its transcriptional co-activator activity could be attenuated by SPINDOC. The first two Tudors are involved in histone methylation readout, while the function of Tudor 3 is largely unknown. Here our structural and binding studies revealed an engagement mode of SPINDOC-Spindlin1, in which a hydrophobic motif of SPINDOC, DOCpep3, stably interacts with Spindlin1 Tudor 3, and two neighboring K/R-rich motifs, DOCpep1 and DOCpep2, bind to the acidic surface of Spindlin1 Tudor 2. Although DOCpep3-Spindlin1 engagement is compatible with histone readout, an extended SPINDOC fragment containing the K/R-rich region attenuates histone or TCF4 binding by Spindlin1 due to introduced competition. This inhibitory effect is more pronounced for weaker binding targets but not for strong ones such as H3 "K4me3-K9me3" bivalent mark. Further ChIP-seq and RT-qPCR indicated that SPINDOC could promote genomic relocation of Spindlin1, thus modulate downstream gene transcription. Collectively, we revealed multivalent engagement between SPINDOC and Spindlin1, in which a hydrophobic motif acts as the primary binding site for stable SPINDOC-Spindlin1 association, while K/R-rich region modulates the target selectivity of Spindlin1 via competitive inhibition, therefore attenuating the transcriptional co-activator activity of Spindlin1.

Turning bad into good: A medium-entropy double perovskite oxide with beneficial surface reconstruction for active and robust cathode of solid oxide fuel cells.

The cathodes of solid oxide fuel cells (SOFCs) often suffer from detrimental cation segregations and associated impurities poisoning, leading to insufficient electroactivity and poor stability. Here we developed a medium-entropy double perovskite GdBa(Co1.2Mn0.2Fe0.2Ni0.2Cu0.2)O5-δ (ME-GBCO) for promising SOFC cathode. The increased configuration entropy can effectively tailor the surface composition with in situ formed active BaCoO3-δ (BCO) species, rather than inert and deleterious BaOx segregation on parent GdBaCo2O5-δ (GBCO) surface. Accordingly, the layered ME-GBCO cathode with beneficial surface reconstruction exhibited not only high oxygen reduction activity but excellent durability against CO2 impurity, enabling it a very attractive cathode for intermediate temperature SOFCs (IT-SOFCs). Our study provides a new idea for development of efficient and durable cathodes via configurational entropy induced rational surface reconstruction.

Oxygen-enriched pitch-derived hierarchically porous carbon toward boosted zinc-ion storage performance.

The lack of cathode materials with satisfactory Zn2+ storage capability substantially hinders the realization of high-performance aqueous zinc-ion hybrid capacitors (ZHCs). Herein, we propose a facile KMnO4 template-assisted KOH activation strategy to prepare a novel oxygen-enriched hierarchically porous carbon (HPC-1-4). This strategy efficiently converts coal tar pitch (CTP) into a well-tuned carbon material with a large specific surface area of 3019 m2 g-1 and a high oxygen content of 9.20 at%, which is conducive to providing rich active sites, rapid charge transport, and appreciable pseudocapacitance for Zn-ion storage. Thus, the as-fabricated HPC-1-4-based aqueous ZHC exhibits prominent performance, including a high gravimetric capacity (206.7 mAh g-1 at 0.25 A g-1), a remarkable energy density (153.4 Wh kg-1 at 184.2 W kg-1), and an impressive power output (15240 W kg-1 at 63.5 Wh kg-1). In-depth ex-situ characterizations indicate that the excellent electrochemical properties of ZHCs are due to the synergistic effect of the Zn2+ adsorption mechanism and reversible chemisorption. In addition, the assembled quasi-solid-state device demonstrates excellent electrochemical stability of up to 100% capacity retention over 50000 cycles, accompanied with a desirable energy density of 115.6 Wh kg-1. The facile preparation method of converting CTP into carbonaceous functional materials has advanced the development of efficient and eco-friendly energy storage technologies.

Degradation Mechanisms of Electrodes Promotes Direct Regeneration of Spent Li-Ion Batteries: A Review.

The rapid growth of electric vehicle use is expected to cause a significant environmental problem in the next few years due to the large number of spent lithium-ion batteries (LIBs). Recycling spent LIBs will not only alleviate the environmental problems but also address the challenge of limited natural resources shortages. While several hydro- and pyrometallurgical processes are developed for recycling different components of spent batteries, direct regeneration presents clear environmental, and economic advantages. The principle of the direct regeneration approach is restoring the electrochemical performance by healing the defective structure of the spent materials. Thus, the development of direct regeneration technology largely depends on the formation mechanism of defects in spent LIBs. This review systematically details the degradation mechanisms and types of defects found in diverse cathode materials, graphite anodes, and current collectors during the battery's lifecycle. Building on this understanding, principles and methodologies for directly rejuvenating materials within spent LIBs are outlined. Also the main challenges and solutions for the large-scale direct regeneration of spent LIBs are proposed. Furthermore, this review aims to pave the way for the direct regeneration of materials in discarded lithium-ion batteries by offering a theoretical foundation and practical guidance.

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

Efficient lattice-based revocable attribute-based encryption against decryption key exposure for cloud file sharing.

Cloud file sharing (CFS) has become one of the important tools for enterprises to reduce technology operating costs and improve their competitiveness. Due to the untrustworthy cloud service provider, access control and security issues for sensitive data have been key problems to be addressed. Current solutions to these issues are largely related to the traditional public key cryptography, access control encryption or attribute-based encryption based on the bilinear mapping. The rapid technological advances in quantum algorithms and quantum computers make us consider the transition from the tradtional cryptographic primitives to the post-quantum counterparts. In response to these problems, we propose a lattice-based Ciphertext-Policy Attribute-Based Encryption(CP-ABE) scheme, which is designed based on the ring learing with error problem, so it is more efficient than that designed based on the learing with error problem. In our scheme, the indirect revocation and binary tree-based data structure are introduced to achieve efficient user revocation and dynamic management of user groups. At the same time, in order to further improve the efficiency of the scheme and realize file sharing across enterprises, the scheme also allows multiple authorities to jointly set up system parameters and manage distribute keys. Furthermore, by re-randomizing the user's private key and update key, we achieve decryption key exposure resistance(DKER) in the scheme. We provide a formal security model and a series of security experiments, which show that our scheme is secure under chosen-plaintext attacks. Experimental simulations and evaluation analyses demonstrate the high efficiency and practicality of our scheme.

A review on multimodal machine learning in medical diagnostics.

Nowadays, the increasing number of medical diagnostic data and clinical data provide more complementary references for doctors to make diagnosis to patients. For example, with medical data, such as electrocardiography (ECG), machine learning algorithms can be used to identify and diagnose heart disease to reduce the workload of doctors. However, ECG data is always exposed to various kinds of noise and interference in reality, and medical diagnostics only based on one-dimensional ECG data is not trustable enough. By extracting new features from other types of medical data, we can implement enhanced recognition methods, called multimodal learning. Multimodal learning helps models to process data from a range of different sources, eliminate the requirement for training each single learning modality, and improve the robustness of models with the diversity of data. Growing number of articles in recent years have been devoted to investigating how to extract data from different sources and build accurate multimodal machine learning models, or deep learning models for medical diagnostics. This paper reviews and summarizes several recent papers that dealing with multimodal machine learning in disease detection, and identify topics for future research.

Development and Experimental Validation of a Novel Prognostic Signature for Gastric Cancer.

BACKGROUND: Gastric cancer is a malignant tumor with high morbidity and mortality. Therefore, the accurate recognition of prognostic molecular markers is the key to improving treatment efficacy and prognosis. METHODS: In this study, we developed a stable and robust signature through a series of processes using machine-learning approaches. This PRGS was further experimentally validated in clinical samples and a gastric cancer cell line. RESULTS: The PRGS is an independent risk factor for overall survival that performs reliably and has a robust utility. Notably, PRGS proteins promote cancer cell proliferation by regulating the cell cycle. Besides, the high-risk group displayed a lower tumor purity, higher immune cell infiltration, and lower oncogenic mutation than the low-PRGS group. CONCLUSIONS: This PRGS could be a powerful and robust tool to improve clinical outcomes for individual gastric cancer patients.

(Tn5-)FISH-based imaging in the era of 3D/spatial genomics.

3D genomics mainly focuses on the 3D position of single genes at the cell level, while spatial genomics focuses more on the tissue level. In this exciting new era of 3D/spatial genomics, half-century old FISH and its derivative methods, including Tn5-FISH, play important roles. In this review, we introduce the Tn5-FISH we developed recently, and present six different applications published by our collaborators and us, based on (Tn5-)FISH, which can be either general BAC clone-based FISH or Tn5-FISH. In these interesting cases, (Tn5-)FISH demonstrated its vigorous ability of targeting sub-chromosomal structures across different diseases and cell lines (leukemia, mESCs (mouse embryonic stem cells), and differentiation cell lines). Serving as an effective tool to image genomic structures at the kilobase level, Tn5-FISH holds great potential to detect chromosomal structures in a high-throughput manner, thus bringing the dawn for new discoveries in the great era of 3D/spatial genomics.