The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8+ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8+ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8+ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8+ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (TTSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-TTSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy.

Interchromosomal Colocalization with Parental Genes Is Linked to the Function and Evolution of Mammalian Retrocopies.

Retrocopies are gene duplicates arising from reverse transcription of mature mRNA transcripts and their insertion back into the genome. While long being regarded as processed pseudogenes, more and more functional retrocopies have been discovered. How the stripped-down retrocopies recover expression capability and become functional paralogs continually intrigues evolutionary biologists. Here, we investigated the function and evolution of retrocopies in the context of 3D genome organization. By mapping retrocopy-parent pairs onto sequencing-based and imaging-based chromatin contact maps in human and mouse cell lines and onto Hi-C interaction maps in 5 other mammals, we found that retrocopies and their parental genes show a higher-than-expected interchromosomal colocalization frequency. The spatial interactions between retrocopies and parental genes occur frequently at loci in active subcompartments and near nuclear speckles. Accordingly, colocalized retrocopies are more actively transcribed and translated and are more evolutionarily conserved than noncolocalized ones. The active transcription of colocalized retrocopies may result from their permissive epigenetic environment and shared regulatory elements with parental genes. Population genetic analysis of retroposed gene copy number variants in human populations revealed that retrocopy insertions are not entirely random in regard to interchromosomal interactions and that colocalized retroposed gene copy number variants are more likely to reach high frequencies, suggesting that both insertion bias and natural selection contribute to the colocalization of retrocopy-parent pairs. Further dissection implies that reduced selection efficacy, rather than positive selection, contributes to the elevated allele frequency of colocalized retroposed gene copy number variants. Overall, our results hint a role of interchromosomal colocalization in the "resurrection" of initially neutral retrocopies.

Single-cell multi-omics profiling reveals key regulatory mechanisms that poise germinal vesicle oocytes for maturation in pigs.

The molecular mechanisms controlling the transition from meiotic arrest to meiotic resumption in mammalian oocytes have not been fully elucidated. Single-cell omics technology provides a new opportunity to decipher the early molecular events of oocyte growth in mammals. Here we focused on analyzing oocytes that were collected from antral follicles in different diameters of porcine pubertal ovaries, and used single-cell M&T-seq technology to analyze the nuclear DNA methylome and cytoplasmic transcriptome in parallel for 62 oocytes. 10× Genomics single-cell transcriptomic analyses were also performed to explore the bi-directional cell-cell communications within antral follicles. A new pipeline, methyConcerto, was developed to specifically and comprehensively characterize the methylation profile and allele-specific methylation events for a single-cell methylome. We characterized the gene expressions and DNA methylations of individual oocyte in porcine antral follicle, and both active and inactive gene's bodies displayed high methylation levels, thereby enabled defining two distinct types of oocytes. Although the methylation levels of Type II were higher than that of Type I, Type II contained nearly two times more of cytoplasmic transcripts than Type I. Moreover, the imprinting methylation patterns of Type II were more dramatically divergent than Type I, and the gene expressions and DNA methylations of Type II were more similar with that of MII oocytes. The crosstalk between granulosa cells and Type II oocytes was active, and these observations revealed that Type II was more poised for maturation. We further confirmed Insulin Receptor Substrate-1 in insulin signaling pathway is a key regulator on maturation by in vitro maturation experiments. Our study provides new insights into the regulatory mechanisms between meiotic arrest and meiotic resumption in mammalian oocytes. We also provide a new analytical package for future single-cell methylomics study.

Intravaginal delivery for CRISPR-Cas9 technology: For example, the treatment of HPV infection.

The increasing incidence of sexually transmitted diseases in women, including human papillomavirus (HPV) infection, has led to the need to develop user-friendly potential prevention methods. At present, although there are several therapeutic parts, none of them has a preventive effect, but they are only limited to providing patients with symptom relief. Researchers have now recognized the need to find effective local preventive agents. One of the potential undiscovered local fungicides is the vaginal delivery of CRISPR/Cas9. CRISPR/Cas9 delivery involves silencing gene expression in a sequence-specific manner in the pathogenic agent, thus showing microbicidal activity. However, vaginal mucosal barrier and physiological changes (such as pH value and variable epithelial thickness in the menstrual cycle) are the main obstacles to effective delivery and cell uptake of CRISPR/Cas9. To enhance the vaginal delivery of CRISPR/Cas9, so far, nano-carrier systems such as lipid delivery systems, macromolecular systems, polymer nanoparticles, aptamers, and cell-penetrating peptides have been extensively studied. In this paper, various nano-carriers and their prospects in the preclinical stage are described, as well as the future significance of CRISPR/Cas9 vaginal delivery based on nano-carriers.

From 1D to 2D: Controllable Preparation of 2D Ni-MOFs for Supercapacitors.

Controllable modulation strategies between one-dimensional (1D) and two-dimensional (2D) structures have been rarely reported for metal-organic frameworks (MOFs). Here, 1D, 1D/2D, and 2D Ni-MOFs can be facilely prepared by adjusting the ratio of Ni2+ and the pyromellitic acid linker. A low-dimensional structure can shorten the transmission distance, while MOFs with a high Ni2+ content can supply rich active sites for oxidation-reduction reactions. The 2D structure Ni-MOF with an optimized Ni2+/pyromellitic acid ratio presents a good performance of 1036 F g-1 at a current density of 1 A g-1 with a comparable rate performance of 62% at 20 A g-1. The study may offer a facile design to control the structure of MOFs for employing in electrochemical energy storage.

Study on detection of CNVs using human whole genome bisulfite sequencing data.

It has been reported that the aberrant DNA methylation may result in copy number variations (CNVs), and the CNVs may alter the levels of DNA methylation. Whole genome bisulfite sequencing (WGBS) is able to generate the sequencing data of DNAs, and shows the potential ability to detect CNVs. However, the evaluations and performances on the detections of CNVs using WGBS data is still unclear. In this study, five software with different strategies for CNV detections, e.g., BreakDancer, cn.mops, CNVnator, DELLY and Pindel, were selected to explore and benchmark the performances of CNV detections with WGBS data. Based on the real (2.62 billion reads) and simulated (12.35 billion reads) WGBS data of humans, we calculated the number, precision, recall, relative ability, memory usage, and running time of CNV detections by 150 times, and tried to figure out the optimal strategy for CNV detections with WGBS data. Based on the real WGBS data, Pindel detected the most deletions and duplications, CNVnator detected the deletions with the highest precision, cn.mops detected the duplications with the highest precision, Pindel detected the deletions with the highest recall, and cn.mops detected the duplications with the highest recall. Based on the simulated WGBS data, BreakDancer detected the most deletions, and cn.mops detected the most duplications. The CNVnator showed the highest precision and recall for both deletions and duplications. In real and simulated WGBS data, the ability of CNVnator to detect CNVs was likely to overtake that in the whole genome sequencing data. Additionally, DELLY and BreakDancer displayed the lowest peak of memory usage and the lest CPU runtime, while CNVnator expressed the highest peak of memory usage and the most CPU runtime. Taken together, CNVnator and cn.mops showed the excellent performances of CNV detections with WGBS data. These results suggested that it was feasible to detect CNVs using WGBS data, and provided the useful information to further investigate both CNVs and DNA methylation using WGBS data alone.

One-Dimensional Co-Carbonate Hydroxide@Ni-MOFs Composite with Super Uniform Core-Shell Heterostructure for Ultrahigh Rate Performance Supercapacitor Electrode.

The insufficient contact between two phases in the heterostructure weakens the coupling interaction effect, which makes it difficult to effectively improve the electrochemical performance. Herein, a Co-carbonate hydroxide@ Ni-metal organic frameworks (Co-CH@Ni-MOFs) composite with super uniform core-shell heterostructure is fabricated by adopting 1D Co-CH nanowires as structuredirecting agents to induce the coating of Ni-MOFs. Both experimental and theoretical calculation results demonstrate that the heterostructure plays a vital role in the high performance of the as-prepared materials. On the one hand, the construction of super uniform core-shell heterostructure can create a large number of interfacial active sites and take advantages of the electrochemical characteristics of each component. On the other hand, the heterostructure can increase the adsorption energy of OH- ions and promote the electrochemical activity for improving the reversible redox reaction kinetics. Based on the aforementioned advantages, the as-fabricated Co-CH@Ni-MOFs electrode exhibits a high specific capacity of 173.1 mAh g-1 (1246 F g-1 ) at 1 A g-1 , an ultrahigh rate capability of 70.3% at 150 A g-1 and excellent cycling stability with 90.1% capacity retention after 10 000 cycles at 10 A g-1 . This study may offer a versatile design for fabricating a MOFs-based heterostructure as energy storage electrodes.

PAL-SLAM: a feature-based SLAM system for a panoramic annular lens.

Simultaneous localization and mapping (SLAM) is widely used in autonomous driving and intelligent robot positioning and navigation. In order to overcome the defects of traditional visual SLAM in rapid motion and bidirectional loop detection, we present a feature-based PAL-SLAM system for a panoramic-annular-lens (PAL) camera in this paper. We use a mask to extract and match features in the annular effective area of the images. A PAL-camera model, based on precise calibration, is used to transform the matched features onto a unit vector for subsequent processing, and a prominent inlier-checking metric is designed as an epipolar constraint in the initialization. After testing on large-scale indoor and outdoor PAL image dataset sequences, comprising of more than 12,000 images, the accuracy of PAL-SLAM is measured as typically below 1 cm. This result holds consistent in conditions when the camera rotates rapidly, or the Global Navigation Satellite System (GNSS) signals are blocked. PAL-SLAM can also detect unidirectional and bidirectional loop closures. Hence it can be used as a supplement or alternative to expensive commercial navigation systems, especially in urban environments where there are many signal obstructions such as buildings and bridges.

Wavefront-coded phase measuring deflectometry for the all-focused measurement.

Phase measuring deflectometry is a powerful measuring method for complex optical surfaces, which captures the reflected fringe images encoded on the screen under the premise of focusing the measured specular surface. Due to the limited depth of field of the camera, the captured images and the measured surface cannot be focused at the same time. To solve the position-angle uncertainty issue, in this Letter, the wavefront coding technology is used to modulate the imaging wavefront of the deflectometry, thereby making the measuring system insensitive to the defocus and other low-order aberration including astigmatism, field curvature, and so on. To obtain the accurate phase, the captured fringe images are deconvoluted using the modulated point spread function to reduce the phase error. Demonstrated with a highly curved spherical surface, the measurement accuracy can be improved by four times. Experiments demonstrate that the proposed method can successfully reconstruct the complex surfaces defocusing the captured images, which can greatly release the focusing requirement and improve measurement accuracy.

ICGEC: a comparative method for measuring epigenetic conservation of genes via the integrated signal from multiple histone modifications between cell types.

BACKGROUND: Histone post-translational modifications play crucial roles in epigenetic regulation of gene expression and are known to be associated with the phenotypic differences of different cell types. Therefore, it is of fundamental importance to dissect the genes and pathways involved in such a phenotypic variation at the level of epigenetics. However, the existing comparative approaches are largely based on the differences, especially the absolute difference in the levels of individual histone modifications of genes under contrasting conditions. Thus, a method for measuring the overall change in the epigenetic circumstance of each gene underpinned by multiple types of histone modifications between cell types is lacking. RESULTS: To address this challenge, we developed ICGEC, a new method for estimating the degree of epigenetic conservation of genes between two cell lines. Different from existing comparative methods, ICGEC provides a reliable score for measuring the relative change in the epigenetic context of corresponding gene between two conditions and simultaneously produces a score for each histone mark. The application of ICGEC to the human embryonic stem cell line H1 and four H1-derived cell lines with available epigenomic data for the same 16 types of histone modifications indicated high robustness and reliability of ICGEC. Furthermore, the analysis of the epigenetically dynamic and conserved genes which were defined based on the ICGEC output results demonstrated that ICGEC can deepen our understanding of the biological processes of cell differentiation to overcome the limitations of traditional expression analysis. Specifically, the ICGEC-derived differentiation-direction-specific genes were shown to have putative functions that are well-matched with cell identity. Additionally, H3K79me1 and H3K27ac were found to be the main histone marks accounting for whether an epigenetically dynamic gene was differentially expressed between two cell lines. CONCLUSIONS: The use of ICGEC creates a convenient and robust way to measure the overall epigenetic conservation of individual genes and marks between two conditions. Thus, it provides a basis for exploring the epigenotype-phenotype relationship. ICGEC can be deemed a state-of-the-art method tailored for comparative epigenomic analysis of changes in cell dynamics.

Design and implementation of a high-performance panoramic annular lens.

In this work, a high-performance panoramic annular lens system designed with a point-by-point method and variable parameter optimization strategies is proposed. Due to the optimization and design, the system maintains a balance among characteristic parameters and can achieve a 360∘×(40∘-95∘) field of view with a 4.34 mm focal length, an f-number of 4.5, and an F-θ distortion of less than 0.5%. Experimental results verify the parameters and demonstrate that the distortion is less than 0.8%, except in some areas with mechanical damage on the ogive surface.

Chromatin Signature and Transcription Factor Binding Provide a Predictive Basis for Understanding Plant Gene Expression.

Chromatin accessibility and post-transcriptional histone modifications play important roles in gene expression regulation. However, little is known about the joint effect of multiple chromatin modifications on the gene expression level in plants, despite that the regulatory roles of individual histone marks such as H3K4me3 in gene expression have been well-documented. By using machine-learning methods, we systematically performed gene expression level prediction based on multiple chromatin modifications data in Arabidopsis and rice. We found that as few as four histone modifications were sufficient to yield good prediction performance, and H3K4me3 and H3K36me3 being the top two predictors with known functions related to transcriptional initiation and elongation, respectively. We demonstrated that the predictive powers differed between protein-coding and non-coding genes as well as between CpG-enriched and CpG-depleted genes. We also showed that the predictive model trained in one tissue or species could be applied to another tissue or species, suggesting shared underlying mechanisms. More interestingly, the gene expression levels of conserved orthologs are easier to predict than the species-specific genes. In addition, chromatin state of distal enhancers was moderately correlated to gene expression but was dispensable if given the chromatin features of the proximal regions of genes. We further extended the analysis to transcription factor (TF) binding data. Strikingly, the combinatorial effects of only a few TFs were roughly fit to gene expression levels in Arabidopsis. Overall, by using quantitative modeling, we provide a comprehensive and unbiased perspective on the epigenetic and TF-mediated regulation of gene expression in plants.

Selaginellin derivatives from Selaginella tamariscina and evaluation for anti-breast cancer activity.

A phytochemical investigation of Selaginella tamariscina led to the isolation of 17 selaginellin derivatives. Their inhibitory activities against breast cancer cells were screened, and preliminary structure-activity relationships were also established. Among them, dimeric selaginellin 17 showed potential activity against MDA-MB-231 cells with an IC50 value of 3.2 ± 0.1 µM, corresponding to 4-fold higher potency than the reference compound 5-FU (IC50 14.8 ± 0.2 µM). Mechanistic studies indicated that 17 could cause G2/M phase arrest in MDA-MB-231 cells and induce apoptosis accompanied by increased ROS levels.

A multi-omic single-cell landscape of cellular diversification in the developing human cerebral cortex.

The vast neuronal diversity in the human neocortex is vital for high-order brain functions, necessitating elucidation of the regulatory mechanisms underlying such unparalleled diversity. However, recent studies have yet to comprehensively reveal the diversity of neurons and the molecular logic of neocortical origin in humans at single-cell resolution through profiling transcriptomic or epigenomic landscapes, owing to the application of unimodal data alone to depict exceedingly heterogeneous populations of neurons. In this study, we generated a comprehensive compendium of the developing human neocortex by simultaneously profiling gene expression and open chromatin from the same cell. We computationally reconstructed the differentiation trajectories of excitatory projection neurons of cortical origin and inferred the regulatory logic governing lineage bifurcation decisions for neuronal diversification. We demonstrated that neuronal diversity arises from progenitor cell lineage specificity and postmitotic differentiation at distinct stages. Our data paves the way for understanding the primarily coordinated regulatory logic for neuronal diversification in the neocortex.

Pig-eRNAdb: a comprehensive enhancer and eRNA dataset of pigs.

Enhancers and the enhancer RNAs (eRNAs) have been strongly implicated in regulations of transcriptions. Based the multi-omics data (ATAC-seq, ChIP-seq and RNA-seq) from public databases, Pig-eRNAdb is a dataset that comprehensively integrates enhancers and eRNAs for pigs using the machine learning strategy, which incorporates 82,399 enhancers and 37,803 eRNAs from 607 samples across 15 tissues of pigs. This user-friendly dataset covers a comprehensive depth of enhancers and eRNAs annotation for pigs. The coordinates of enhancers and the expression patterns of eRNAs are downloadable. Besides, thousands of regulators on eRNAs, the target genes of eRNAs, the tissue-specific eRNAs, and the housekeeping eRNAs are also accessible as well as the sequence similarity of eRNAs with humans. Moreover, the tissue-specific eRNA-trait associations encompass 652 traits are also provided. It will crucially facilitate investigations on enhancers and eRNAs with Pig-eRNAdb as a reference dataset in pigs.

CRISPR/Cas9 for hepatitis B virus infection treatment.

Hepatitis B virus (HBV) infection remains a global health challenge. Despite the availability of effective preventive vaccines, millions of people are at risk of cirrhosis and hepatocellular carcinoma. Current drug therapies inhibit viral replication, slow the progression of liver fibrosis and reduce infectivity, but they rarely remove the covalently sealed circular DNA (cccDNA) of the virus that causes HBV persistence. Alternative treatment strategies, including those based on CRISPR/cas9 knockout virus gene, can effectively inhibit HBV replication, so it has a good prospect. During chronic infection, some virus gene knockouts based on CRISPR/cas9 may even lead to cccDNA inactivation. This paper reviews the progress of different HBV CRISPR/cas9, vectors for delivering to the liver, and the current situation of preclinical and clinical research.

Deciphering Cellular Heterogeneity and Communication Patterns in Porcine Antral Follicles by Single-Cell RNA Sequencing.

The antral follicle stage is a critical period in mammalian oocyte maturation, marked by complex interactions between oocyte development and neighboring granulosa cells. Understanding the heterogeneity and communication patterns of granulosa cells within antral follicles is crucial for deciphering their roles in follicle development and oocyte maturation. Here, we employed single-cell RNA-sequencing to explore the molecular and cellular characteristics of porcine antral follicles. Our analysis revealed distinct subpopulations within mural and cumulus granulosa cells, indicating diverse cellular states and functions within the follicles. Functional enrichment analysis unveiled the involvement of specific subpopulations in steroid biosynthesis, cumulus expansion, and cellular communication. Moreover, comparing mature and less mature follicles highlighted differences in cell distribution and functions, indicating developmental-specific variations. Our findings shed light on the intricate cellular heterogeneity and communication network within porcine antral follicles, providing valuable insights into the regulation of follicle development and oocyte maturation in pigs. These results hold promise for improving pig reproductive efficiency and advancing human reproductive medicine.

A pharmacovigilance study of etoposide in the FDA adverse event reporting system (FAERS) database, what does the real world say?

Introduction: Etoposide is a broad-spectrum antitumor drug that has been extensively studied in clinical trials. However, limited information is available regarding its real-world adverse reactions. Therefore, this study aimed to assess and evaluate etoposide-related adverse events in a real-world setting by using data mining method on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Through the analysis of 16,134,686 reports in the FAERS database, a total of 9,892 reports of etoposide-related adverse drug events (ADEs) were identified. To determine the significance of these ADEs, various disproportionality analysis algorithms were applied, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms. Results: As a result, 478 significant disproportionality preferred terms (PTs) that were identified by all four algorithms were retained. These PTs included commonly reported adverse events such as thrombocytopenia, leukopenia, anemia, stomatitis, and pneumonitis, which align with those documented in the drug's instructions and previous clinical trials. However, our analysis also uncovered unexpected and significant ADEs, including thrombotic microangiopathy, ototoxicity, second primary malignancy, nephropathy toxic, and ovarian failure. Furthermore, we examined the time-to-onset (TTO) of these ADEs using the Weibull distribution test and found that the median TTO for etoposide-associated ADEs was 10 days (interquartile range [IQR] 2-32 days). The majority of cases occurred within the first month (73.8%) after etoposide administration. Additionally, our analysis revealed specific high-risk signals for males, such as pneumonia and cardiac infarction, while females showed signals for drug resistance and ototoxicity. Discussion: These findings provide valuable insight into the occurrence of ADEs following etoposide initiation, which can potentially support clinical monitoring and risk identification efforts.

Synthesis of the Ni2P-Co Mott-Schottky Junction as an Electrocatalyst to Boost Sulfur Conversion Kinetics and Application in Separator Modification in Li-S Batteries.

To overcome the shuttling effect and sluggish conversion kinetics of polysulfides, a large number of catalysts have been designed for lithium-sulfur (Li-S) batteries. Herein, a Mott-Schottky junction catalyst composed of Co nanoparticles and Ni2P was designed to improve polysulfide kinetics. Our investigations reveal the rearrangement of charges at the Schottky junction interface and the construction of the built-in electric field are crucial for lowering the activation energy of the dissolved Li2Sn reduction and Li2S nucleation reaction. Furthermore, a series of experimental and electrochemical tests were performed to demonstrate that the Schottky catalytic effect enhanced the synergistic catalytic effect. With a Ni2P-Co@CNT catalyst, the battery exhibits an initial specific capacity of 874 mAh g-1 at a rate of 4.0 C, and the decay rate per cycle is 0.049% in 700 cycles. Meanwhile, the battery shows 0.118% decay rate per cycle at 0.5 C in 100 cycles at a high sulfur loading of 10 mg cm-2. The Schottky heterojunction structure proposed here has been shown to have a good catalytic effect on the reduction of Li2Sn and nucleation of Li2S, which provides a profound guidance for efficient and rational catalyst design.

Nanosheet-assembled NiCo-LDH hollow spheres as high-performance electrodes for supercapacitors.

Layered double hydroxides (LDHs) have been considered as favorable pseudocapacitive electrode materials for supercapacitors due to their tunable layered structure/compositions and low cost. Here, we report the NiCo-LDH hollow spheres prepared with Co-glycerate as the sacrificial template and cobalt source. The hollow spheres are assembled with frizzy NiCo-LDH nanosheets, where the hollow structure can inhibit agglomeration of the LDH nanosheets to expose more active sites and shorten the diffusion path of electrolyte ions. The prepared NiCo-LDH hollow spheres show a high specific capacitance of 1962 F g-1 at 1 A g-1 and good capacitance retention rate of 66.4 % at 30 A g-1. The asymmetric supercapacitors fabricated using NiCo-LDH hollow spheres as positive electrode yields a large energy density 62.9 Wh kg-1 at the power density of 0.8 kW kg-1. This research may develop a facile synthesis way to prepare LDH hollow spheres for supercapacitors.