An Analysis of the Vibration Transmission Properties of Assemblies Using Honeycomb Paperboard and Expanded Polyethylene.

In the process of logistics, shock and vibration are the most important factors contributing to product damage. Assembling honeycomb paperboard and EPE is commonly used to provide cushioning and anti-vibration effects to materials. Therefore, it is necessary to study the vibration transmission properties of this kind of assembly in the anti-vibration process. The aim of this paper was to experimentally determine the vibration transmission properties of assemblies with honeycomb paperboard and expanded polyethylene (EPE). Through a sinusoidal sweep vibration test of this assembly, the vibration transmission characteristic curves of assemblies with honeycomb paperboard and EPE of different thicknesses were obtained and compared. Assuming the assembly and mass block as a single degree of freedom with a small damping linear system, the damping energy dissipation of the assembly and the resonance frequency were obtained. The vibration transmission property curves of the assembly can be divided into four regions. With an excitation acceleration of 0.5 g and a honeycomb paperboard with a thickness of 60 mm (F60), the vibration transmission rate and the resonance frequency-of the material dampened with EPE at a thickness of 60 mm (E60), and the assembly (F30/E30) with a 30 mm thick honeycomb paperboard and 30 mm thick EPE-increased by -2.5% and -17.5%, -86.9% and 79.3%, and -95.9% and -85.7%, respectively. Compared to the assembly with 20 mm thick honeycomb and 20 mm thick EPE (F20/E20), the vibration transmission rate, the resonance frequency, and the material damping and damping energy dissipation of F40/E20, F30/E30, and F20/E40 increased by 75.6%, 48.3%, and 66.1%; 1.2%, -21.5%, and -38.9%; 241.5%, 82.8%, and 13.3%; and 12.5%, 98.9%, and 106.8%, respectively. Compared to F60 and E60, the damping energy dissipation of F30/E30 increased by 2816.7% and 133.3%, respectively. The assembly of F30/E30 has the smallest vibration transmission rate and the most vibration energy dissipation among these assemblies. This means that the assembly of F30/E30 absorbs the most external vibration energy, while the acceleration that is transmitted to the internal product is minimal. Therefore, in the design of cushioning packaging, according to the characteristics and natural frequency of the internal products, an appropriate assembly can be selected, which should have a lower vibration transmission rate and more vibration energy dissipation, and should not resonate with the internal product. This will provide a theoretical basis for the design of cushioning packaging.

Analysis of the Dynamic Cushioning Property of Expanded Polyethylene Based on the Stress-Energy Method.

This paper aimed to experimentally clarify the dynamic crushing performance of expanded polyethylene (EPE) and analyze the influence of thickness and dropping height on its mechanical behavior based on the stress-energy method. Hence, a series of impact tests are carried out on EPE foams with different thicknesses and dropping heights. The maximum acceleration, static stress, dynamic stress and dynamic energy of EPE specimens are obtained through a dynamic impact test. Then, according to the principle of the stress-energy method, the functional relationship between dynamic stress and dynamic energy is obtained through exponential fitting and polynomial fitting, and the cushion material constants a, b and c are determined. The maximum acceleration-static stress curves of any thickness and dropping height can be further fitted. By the equipartition energy domain method, the range of static stress can be expanded, which is very fast and convenient. When analyzing the influence of thickness and dropping height on the dynamic cushioning performance curves of EPE, it is found that at the same drop height, with the increase of thickness, the opening of the curve gradually becomes larger. The minimum point on the maximum acceleration-static stress curve also decreases with the increase of the thickness. When the dropping height is 400 mm, compared to foam with a thickness of 60 mm, the tested maximum acceleration value of the lowest point of the specimen with a thickness of 40 mm increased by 45.3%, and the static stress is both 5.5 kPa. When the thickness of the specimen is 50 mm, compared to the dropping height of 300 mm, the tested maximum acceleration value of the lowest point of the specimen with a dropping height of 600 mm increased by 93.3%. Therefore, the dynamic cushioning performance curve of EPE foams can be quickly obtained by the stress-energy method when the precision requirement is not high, which provides a theoretical basis for the design of cushion packaging.

Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies.

Background: Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma (ICC) patients. In this study, we developed a methylation signature that precisely predicts overall survival (OS) after surgery. Methods: An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing (WGBS) was conducted for two independent cohorts (discovery cohort, n=164; validation cohort, n=170) from three hepatobiliary centers in China. By referring to differentially methylated regions (DMRs), we proposed the concept of prognostically methylated regions (PMRs), which were composed of consecutive prognostically methylated CpGs (PMCs). Using machine learning strategies (Random Forest and the least absolute shrinkage and selector regression), a prognostic methylation score (PMS) was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort. Results: The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74, respectively. In the whole cohort, the PMS was an independent predictor of OS [hazard ratio (HR) =8.12; 95% confidence interval (CI): 5.48-12.04; P<0.001], and the C-index (0.78) of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine (JHUSM) nomogram (0.69, P<0.001), the Eastern Hepatobiliary Surgery Hospital (EHBSH) nomogram (0.67, P<0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system (0.61, P<0.001), and MEGNA prognostic score (0.60, P<0.001). The patients in quartile 4 of PMS could benefit from adjuvant therapy (AT) (HR =0.54; 95% CI: 0.32-0.91; log-rank P=0.043), whereas those in the quartiles 1-3 could not. However, other nomograms and staging system failed to do so. Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors, pathway activation, and immune microenvironment. Conclusions: The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients, and might facilitate decisions in treatment of ICC patients.

Pan-cancer Analysis Reveals Cancer-dependent Expression of SOX17 and Associated Clinical Outcomes.

BACKGROUND/AIM: SRY-box containing gene 17 (SOX17) plays a pivotal role in cancer onset and progression and is considered a potential target for cancer diagnosis and treatment. However, the expression pattern of SOX17 in cancer and its clinical relevance remains unknown. Here, we explored the relationship between the expression of SOX17 and drug response by examining SOX17 expression patterns across multiple cancer types. MATERIALS AND METHODS: Single-cell and bulk RNA-seq analyses were used to explore the expression profile of SOX17. Analysis results were verified with qPCR and immunohistochemistry. Survival, drug response, and co-expression analyses were performed to illustrate its correlation with clinical outcomes. RESULTS: The results revealed that abnormal expression of SOX17 is highly heterogenous across multiple cancer types, indicating that SOX17 manifests as a cancer type-dependent feature. Furthermore, the expression pattern of SOX17 is also associated with cancer prognosis in certain cancer types. Strong SOX17 expression correlates with the potency of small molecule drugs that affect PI3K/mTOR signaling. FGF18, a gene highly relevant to SOX17, is involved in the PI3K-AKT signaling pathway. Single-cell RNA-seq analysis demonstrated that SOX17 is mainly expressed in endothelial cells and barely expressed in other cells but spreads to other cell types during the development of ovarian cancer. CONCLUSION: Our study revealed the expression pattern of SOX17 in pan-cancer through bulk and single-cell RNA-seq analyses and determined that SOX17 is related to the diagnosis, staging, and prognosis of some tumors. These findings have clinical implications and may help identify mechanistic pathways amenable to pharmacological interventions.

Crushing Responses of Expanded Polypropylene Foam.

This paper aimed to experimentally clarify the crushing mechanism and performance of expanded polypropylene foam (EPP) and analyze the influence of density and thickness on its mechanical behavior and energy absorption properties under static crushing loadings. Hence, a series of compression tests were carried out on EPP foams with different densities and thicknesses. For foam with a density of 60 kg/m3, the mean crushing strength, energy absorption (Ea), energy absorption efficiency (Ef), specific energy absorption (SEA), and energy absorption per unit volume (w) increased by 245.3%, 187.2%, 42.3%, 54.3%, and 242.8%, respectively, compared to foam with a density of 20 kg/m3. Meanwhile, compared to foam with a thickness of 30 mm, the mean crushing strength, energy absorption (Ea), energy absorption efficiency (Ef), SEA, and energy absorption per unit volume (w) for foam with a thickness of 75 mm increased by 53.3%, 25.2%, -10.8%, -4.7%, and -10.6%, respectively. The results show that foam density has a significantly greater influence on static compressive performance than foam thickness. The microstructures of the EPP foam before and after static compression were compared by observing with a scanning electron microscope (SEM), and the failure mechanism was analyzed. Results showed that the load and energy as well as the deformation and instability processes of its cells were transferred layer by layer. The influence of density on the degree of destruction of the internal cells was obvious. Due to its larger mass and larger internal damping, thicker foams were less damaged, and less deformation was produced. Additionally, the EPP foam exhibited a considerable ability to recover after compression.

Mechanical Behavior of Closed-Cell Ethylene-Vinyl Acetate Foam under Compression.

The static and dynamic compressions of closed-cell ethylene-vinyl acetate (EVA) foams with different densities were conducted under various strain rates. The stress-strain curves were processed to determine the corresponding curves of energy absorption per unit volume and energy absorption efficiency, and energy absorption diagrams were produced. The influences of density and strain rate on the elastic modulus, yield strength, energy absorption per unit volume, optimal strain, densification strain, and energy absorption diagrams were analyzed and discussed. The whole stress-strain curve can be fitted with the Rusch formula. The strain rate does not change the shape of stress-strain curve, and has little influence on the elastic modulus. There exists the optimal density of EVA foam corresponding to its maximum energy absorption efficiency. Under a fixed strain rate, the optical energy absorption per unit volume is proportional to the optical stress on the envelope line in the energy absorption diagrams of EVA foams with different densities. The change in strain rate leads to the envelope line in the energy absorption diagrams of EVA foams with a given density having the larger slope and a negative intercept where the optical energy absorption per unit volume relies linearly on the optical stress. The empirical formulas of elastic modulus, yield strength, optimal strain, and envelope lines and their slopes are derived from the tested results.

Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas.

Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs (PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies.

Deficiency of a novel lncRNA-HRAT protects against myocardial ischemia reperfusion injury by targeting miR-370-3p/RNF41 pathway.

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) contribute to myocardial ischemia/reperfusion (I/R) injury. However, the underlying mechanisms by which lncRNAs modulate myocardial I/R injury have not been thoroughly examined and require further investigation. A novel lncRNA named lncRNA-hypoxia/reoxygenation (H/R)-associated transcript (lncRNA-HRAT) was identified by RNA sequencing analysis. The expression of lncRNA-HRAT exhibited a significant increase in the I/R mice hearts and cardiomyocytes treated with H/R. LncRNA-HRAT overexpression facilitates H/R-induced cardiomyocyte apoptosis. Furthermore, cardiomyocyte-specific deficiency of lncRNA-HRAT in vivo after I/R decreased creatine kinase (CK) release in the serum, reduced myocardial infarct area, and improved cardiac dysfunction. Molecular mechanistic investigations revealed that lncRNA-HRAT serves as a competing endogenous RNA (ceRNA) of miR-370-3p, thus upregulating the expression of ring finger protein 41 (RNF41), thereby aggravating apoptosis in cardiomyocytes induced by H/R. This study revealed that the lncRNA-HRAT/miR-370-3p/RNF41 pathway regulates cardiomyocyte apoptosis and myocardial injury. These findings suggest that targeted inhibition of lncRNA-HRAT may offer a novel therapeutic method to prevent myocardial I/R injury.

Single-Cell RNA-Sequencing Atlas Reveals the Tumor Microenvironment of Metastatic High-Grade Serous Ovarian Carcinoma.

Ovarian cancer is the most common and lethal gynecological tumor in women worldwide. High-grade serous ovarian carcinoma (HGSOC) is one of the histological subtypes of epithelial ovarian cancer, accounting for 70%. It often occurs at later stages associated with a more fatal prognosis than endometrioid carcinomas (EC), another subtype of epithelial ovarian cancer. However, the molecular mechanism and biology underlying the metastatic HGSOC (HG_M) immunophenotype remain poorly elusive. Here, we performed single-cell RNA sequencing analyses of primary HGSOC (HG_P) samples, metastatic HGSOC (HG_M) samples, and endometrioid carcinomas (EC) samples. We found that ERBB2 and HOXB-AS3 genes were more amplified in metastasis tumors than in primary tumors. Notably, high-grade serous ovarian cancer metastases are accompanied by dysregulation of multiple pathways. Malignant cells with features of epithelial-mesenchymal transition (EMT) affiliated with poor overall survival were identified. In addition, cancer-associated fibroblasts with EMT-program were enriched in HG_M, participating in angiogenesis and immune regulation, such as IL6/STAT3 pathway activity. Compared with ECs, HGSOCs exhibited higher T cell infiltration. PRDM1 regulators may be involved in T cell exhaustion in ovarian cancer. The CX3CR1_macro subpopulation may play a role in promoting tumor progression in ovarian cancer with high expression of BAG3, IL1B, and VEGFA. The new targets we discovered in this study will be useful in the future, providing guidance on the treatment of ovarian cancer.

TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation.

Existing knowledge of the role of epigenetic modifiers in pancreas development has exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine specification remains obscure. We set out to tackle this issue using a human embryonic stem cell (hESC) differentiation system, in which TET1/TET2/TET3 triple knockout cells display severe defects in pancreatic ß-cell specification. The integrative whole-genome analysis identifies unique cell-type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and remarkable enrichment of FOXA2, a pioneer transcription factor essential for pancreatic endoderm specification. Intriguingly, TET depletion leads to significant changes in FOXA2 binding at the pancreatic progenitor stage, in which gene loci with decreased FOXA2 binding feature low levels of active chromatin modifications and enriches for bHLH motifs. Transduction of full-length TET1 but not the TET1-catalytic-domain in TET-deficient cells effectively rescues ß-cell differentiation accompanied by restoring PAX4 hypomethylation. Taking these findings together with the defective generation of functional ß-cells upon TET1-inactivation, our study unveils an essential role of TET1-dependent demethylation in establishing ß-cell identity. Moreover, we discover a physical interaction between TET1 and FOXA2 in endodermal lineage intermediates, which provides a mechanistic clue regarding the complex crosstalk between TET dioxygenases and pioneer transcription factors in epigenetic regulation during pancreas specification.

Novel Allele Detection Tool Benchmark and Application With Antibody Repertoire Sequencing Dataset.

Detailed knowledge of the diverse immunoglobulin germline genes is critical for the study of humoral immunity. Hundreds of alleles have been discovered by analyzing antibody repertoire sequencing (Rep-seq or Ig-seq) data via multiple novel allele detection tools (NADTs). However, the performance of these NADTs through antibody sequences with intrinsic somatic hypermutations (SHMs) is unclear. Here, we developed a tool to simulate repertoires by integrating the full spectrum features of an antibody repertoire such as germline gene usage, junctional modification, position-specific SHM and clonal expansion based on 2152 high-quality datasets. We then systematically evaluated these NADTs using both simulated and genuine Ig-seq datasets. Finally, we applied these NADTs to 687 Ig-seq datasets and identified 43 novel allele candidates (NACs) using defined criteria. Twenty-five alleles were validated through findings of other sources. In addition to the NACs detected, our simulation tool, the results of our comparison, and the streamline of this process may benefit further humoral immunity studies via Ig-seq.

Dietary spinach reshapes the gut microbiome in an Apc-mutant genetic background: mechanistic insights from integrated multi-omics.

Complex interrelationships govern the dynamic interactions between gut microbes, the host, and exogenous drivers of disease outcome. A multi-omics approach to cancer prevention by spinach (SPI) was pursued for the first time in the polyposis in rat colon (Pirc) model. SPI fed for 26 weeks (10% w/w, freeze-dried in the diet) exhibited significant antitumor efficacy and, in the Apc-mutant genetic background, ß-catenin remained highly overexpressed in adenomatous polyps. However, in both wild type and Apc-mutant rats, increased gut microbiome diversity after SPI consumption coincided with reversal of taxonomic composition. Metagenomic prediction implicated linoleate and butanoate metabolism, tricarboxylic acid cycle, and pathways in cancer, which was supported by transcriptomic and metabolomic analyses. Thus, tumor suppression by SPI involved marked reshaping of the gut microbiome along with changes in host RNA-miRNA networks. When colon polyps were compared with matched normal-looking tissues via metabolomics, anticancer outcomes were linked to SPI-derived linoleate bioactives with known anti-inflammatory/ proapoptotic mechanisms, as well as N-aceto-2-hydroxybutanoate, consistent with altered butanoate metabolism stemming from increased α-diversity of the gut microbiome. In colon tumors from SPI-fed rats, L-glutamate and N-acetylneuraminate also were reduced, implicating altered mitochondrial energetics and cell surface glycans involved in oncogenic signaling networks and immune evasion. In conclusion, a multi-omics approach to cancer prevention by SPI provided mechanistic support for linoleate and butanoate metabolism, as well as tumor-associated changes in L-glutamate and N-acetylneuraminate. Additional factors, such as the fiber content, also warrant further investigation with a view to delaying colectomy and drug intervention in at-risk patients.

Antibody upstream sequence diversity and its biological implications revealed by repertoire sequencing.

The sequence upstream of the antibody variable region (antibody upstream sequence [AUS]) consists of a 5' untranslated region (5' UTR) and a preceding leader region. The sequence variations in AUS affect antibody engineering and PCR based antibody quantification and may also be implicated in mRNA transcription and translation. However, the diversity of AUSs remains elusive. Using 5' rapid amplification of cDNA ends and high-throughput antibody repertoire sequencing technique, we acquired full-length AUSs for human, rhesus macaque, cynomolgus macaque, mouse, and rat. We designed a bioinformatics pipeline and identified 3307 unique AUSs, corresponding to 3026 and 1457 unique sequences for 5' UTR and leader region, respectively. Comparative analysis indicated that 928 (63.69%) leader sequences are novel relative to those recorded in the international ImMunoGeneTics information system. Evolutionarily, leader sequences are more conserved than 5' UTR and seem to coevolve with their downstream V genes. Besides, single-nucleotide polymorphisms are position dependent for leader regions and may contribute to the functional reversal of the downstream V genes. Finally, the AUGs in AUSs were found to have little impact on gene expression. Taken together, our findings can facilitate primer design for capturing antibodies efficiently and provide a valuable resource for antibody engineering and molecule-level antibody studies.

Genome-wide DNA methylation profiling of leukocytes identifies CpG methylation signatures of aggressive prostate cancer.

Most of screening-detected prostate cancer (PCa) are indolent and not lethal. Biomarkers that can predict aggressive diseases independently of clinical features are needed to improve risk stratification of localized PCa patients and reduce overtreatment. We aimed to identify leukocyte DNA methylation differences between clinically defined aggressive and non-aggressive PCa. We performed whole genome DNA methylation profiling in leukocyte DNA from 287 PCa patients with Gleason Score (GS) 6 and ≥8 using Illumina 450k methylation arrays. We observed a global hypomethylation in GS≥8 patients compared to GS=6 PCa patients; in contrast, the methylation level in core promoter and exon 1 region was significantly higher in GS≥8 patients than GS=6 PCa. We then performed 5-fold cross validated random forest model training on 1,459 differentially methylated CpG Probes (DMPs) with false discovery rate (FDR) <0.01 between GS=6 and GS≥8 groups. The power of the predictive model was further reinforced by ranking the DMPs with Decreased Gini and re-train the model with the top 97 DMPs (Testing AUC=0.920, predict accuracy =0.847). In conclusion, we identified a CpG methylation signature in leukocyte DNA that is associated with aggressive clinical features of PCa at diagnosis.

Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes.

Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8+ T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8+ T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth. SIGNIFICANCE: This study suggests that ablation of TET2+ from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.

LiBis: an ultrasensitive alignment augmentation for low-input bisulfite sequencing.

The cell-free DNA (cfDNA) methylation profile in liquid biopsy has been utilized to diagnose early-stage disease and estimate therapy response. However, typical clinical procedures are capable of purifying only very small amounts of cfDNA. Whole-genome bisulfite sequencing (WGBS) is the gold standard for measuring DNA methylation; however, WGBS using small amounts of fragmented DNA introduces a critical challenge for data analysis, namely a low-mapping ratio. The resulting low sequencing depth and low coverage of CpG sites genome-wide is a bottleneck for the clinical application of cfDNA-based WGBS assays. We developed LiBis (Low-input Bisulfite Sequencing), a novel method for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpGs and the precision in quantifying the methylation status of individual CpG sites. LiBis significantly improved the cost efficiency of low-input WGBS experiments by dynamically removing contamination introduced by random priming. The high sensitivity and cost effectiveness afforded by LiBis for low-input samples will allow the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy.

The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin.

Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive MD, elevated serum creatine kinase, heart dilation, blood vessel irregularity and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with agrin (AGR-H19) and nifenazone competed with or inhibited TRIM63. Dmd C3333Y animals, induced-pluripotent-stem-cell-derived skeletal muscle cells from patients with Becker MD and mdx mice subjected to exon skipping exhibited inhibited dystrophin degradation, preserved skeletal and cardiac muscle histology, and improved strength and heart function following AGR-H19 or nifenazone treatment. Our study paves the way for meaningful targeted therapeutics for Becker MD and for certain patients with Duchenne MD.

Reliable tumor detection by whole-genome methylation sequencing of cell-free DNA in cerebrospinal fluid of pediatric medulloblastoma.

Medulloblastoma (MB), the most common form of pediatric brain malignancy, has a low frequency of oncogenic mutations but pronouncedly abnormal DNA methylation changes. Epigenetic analysis of circulating cell-free tumor DNA (ctDNA) by liquid biopsy offers an approach for real-time monitoring of tumor status without tumor dissection. In this study, we identified 6598 differentially methylated CpGs in both MB tumors and the ctDNA isolated from matched cerebrospinal fluid (CSF) compared with normal cerebellum, which could be used to detect MB tumor occurrence and determine its subtype. Furthermore, DNA methylation changes in serial CSF samples could be used to monitor the treatment response and tumor recurrence. Integrating our data with large public datasets, we identified reliable MB DNA methylation signatures in ctDNA that have potential diagnostic and prognostic values. Our study sets the stage for exploiting epigenetic markers in CSF to improve the clinical management of patients with MB.

Publisher Correction: Integrated analysis of a compendium of RNA-Seq datasets for splicing factors.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.