UTX condensation underlies its tumour-suppressive activity.

UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.

DNA fragility at topologically associated domain boundaries is promoted by alternative DNA secondary structure and topoisomerase II activity.

CCCTC-binding factor (CTCF) binding sites are hotspots of genome instability. Although many factors have been associated with CTCF binding site fragility, no study has integrated all fragility-related factors to understand the mechanism(s) of how they work together. Using an unbiased, genome-wide approach, we found that DNA double-strand breaks (DSBs) are enriched at strong, but not weak, CTCF binding sites in five human cell types. Energetically favorable alternative DNA secondary structures underlie strong CTCF binding sites. These structures coincided with the location of topoisomerase II (TOP2) cleavage complex, suggesting that DNA secondary structure acts as a recognition sequence for TOP2 binding and cleavage at CTCF binding sites. Furthermore, CTCF knockdown significantly increased DSBs at strong CTCF binding sites and at CTCF sites that are located at topologically associated domain (TAD) boundaries. TAD boundary-associated CTCF sites that lost CTCF upon knockdown displayed increased DSBs when compared to the gained sites, and those lost sites are overrepresented with G-quadruplexes, suggesting that the structures act as boundary insulators in the absence of CTCF, and contribute to increased DSBs. These results model how alternative DNA secondary structures facilitate recruitment of TOP2 to CTCF binding sites, providing mechanistic insight into DNA fragility at CTCF binding sites.

Fob1-dependent condensin recruitment and loop extrusion on yeast chromosome III.

Despite recent advances in single-molecule and structural analysis of condensin activity in vitro, mechanisms of functional condensin loading and loop extrusion that lead to specific chromosomal organization remain unclear. In Saccharomyces cerevisiae, the most prominent condensin loading site is the rDNA locus on chromosome XII, but its repetitiveness deters rigorous analysis of individual genes. An equally prominent non-rDNA condensin site is located on chromosome III (chrIII). It lies in the promoter of a putative non-coding RNA gene called RDT1, which is in a segment of the recombination enhancer (RE) that dictates MATa-specific chrIII organization. Here, we unexpectedly find that condensin is recruited to the RDT1 promoter in MATa cells through hierarchical interactions with Fob1, Tof2, and cohibin (Lrs4/Csm1), a set of nucleolar factors that also recruit condensin to the rDNA. Fob1 directly binds to this locus in vitro, while its binding in vivo depends on an adjacent Mcm1/α2 binding site that provides MATa cell specificity. We also uncover evidence for condensin-driven loop extrusion anchored by Fob1 and cohibin at RDT1 that unidirectionally extends toward MATa on the right arm of chrIII, supporting donor preference during mating-type switching. S. cerevisiae chrIII therefore provides a new platform for the study of programmed condensin-mediated chromosome conformation.

Multiresponse Liquid Metal Bionic Flexible Actuator.

The flexible actuator has attracted significant interest for its ability to respond flexibly to external stimuli, especially for renewable natural energy sources. However, the flexible actuator faces issues such as inadequate sensitivity and inability to achieve synergistic responses. Therefore, we prepared a highly sensitive flexible actuator by mixing liquid metal (LM) with poly(vinylpyrrolidone) (PVP), graphene oxide (GO), and coating the resulting mixtures onto poly(ethylene terephthalate) (PET) substrate materials using the rod coating process. The flexible actuator responds quickly to near-infrared light and humidity and can be rapidly transformed from flat to curved with a maximum angular change of 540°. By demonstrating the flexible actuator in action, it can be used to create a crawling robot that mimics the movement of an inchworm on a leaf, as well as a gripper capable of lifting objects 5 times its weight, and a crawling robot that moves forward, turns left, and then right. Flexible actuators hold significant promise for applications in emerging fields such as advanced bionics and artificial intelligence.

Daytime sleepiness is associated with increased coronary plaque burden among patients with obstructive sleep apnea.

PURPOSE: To investigate the cross-sectional associations of daytime sleepiness with coronary plaque volume and composition in patients with obstructive sleep apnea (OSA), and whether or not these associations are modified by age, gender, and obesity. METHODS: Patients who were confirmed with OSA through respiratory polygraphy and also underwent coronary CTA at a tertiary hospital were consecutively enrolled. The interval between the sleep monitoring and coronary CTA scan was < 3 months. Every patient completed the Epworth sleepiness scale (ESS) to assess daytime sleepiness, and an ESS score of ≥ 11 was recognized as excessive daytime sleepiness (EDS). Coronary plaque volume and composition were measured using semi-automatic software. RESULTS: Of the 394 patients with OSA (median [IQR] age, 56.0 [49.0-64.0] years; median [IQR] body mass index, 27.9 [25.5-30.2] kg/m2; median [IQR] apnea-hypopnea index, 21.3 [11.7, 36.3] events/h), a total of 200 patients had EDS. In the overall participants, a significant dose-response relationship between ESS scores and low-attenuation plaque volume was found in the fully adjusted model (P = 0.019). Further analysis demonstrated that there was a significant interactive effect of ESS levels and obesity on coronary plaque volume (all P values for interaction analysis < 0.05). Specifically, ESS levels were associated with total plaque volume, volumes of noncalcified, low-attenuation, and calcified plaque (P = 0.008, 0.006, 0.005, and 0.043 respectively) in obese patients with OSA. CONCLUSION: Daytime sleepiness is significantly correlated with increased coronary plaque burden among patients with OSA. Thus, clinicians should recognize that patients with OSA reporting high ESS scores, especially those with obesity, are more prone to experience adverse coronary events.

BART3D: inferring transcriptional regulators associated with differential chromatin interactions from Hi-C data.

SUMMARY: Identification of functional transcriptional regulators (TRs) associated with chromatin interactions is an important problem in studies of 3-dimensional genome organization and gene regulation. Direct inference of TR binding has been limited by the resolution of Hi-C data. Here, we present BART3D, a computational method for inferring TRs associated with genome-wide differential chromatin interactions by comparing Hi-C maps from two states, leveraging public ChIP-seq data for human and mouse. We demonstrate that BART3D can detect relevant TRs from dynamic Hi-C profiles with TR perturbation or cell differentiation. BART3D can be a useful tool in 3D genome data analysis and functional genomics research. AVAILABILITY AND IMPLEMENTATION: BART3D is implemented in Python and the source code is available at https://github.com/zanglab/bart3d. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Assessing acute myeloid leukemia susceptibility in rearrangement-driven patients by DNA breakage at topoisomerase II and CCCTC-binding factor/cohesin binding sites.

An initiating DNA double strand break (DSB) event precedes the formation of cancer-driven chromosomal abnormalities, such as gene rearrangements. Therefore, measuring DNA breaks at rearrangement-participating regions can provide a unique tool to identify and characterize susceptible individuals. Here, we developed a highly sensitive and low-input DNA break mapping method, the first of its kind for patient samples. We then measured genome-wide DNA breakage in normal cells of acute myeloid leukemia (AML) patients with KMT2A (previously MLL) rearrangements, compared to that of nonfusion AML individuals, as a means to evaluate individual susceptibility to gene rearrangements. DNA breakage at the KMT2A gene region was significantly greater in fusion-driven remission individuals, as compared to nonfusion individuals. Moreover, we identified select topoisomerase II (TOP2)-sensitive and CCCTC-binding factor (CTCF)/cohesin-binding sites with preferential DNA breakage in fusion-driven patients. Importantly, measuring DSBs at these sites, in addition to the KMT2A gene region, provided greater predictive power when assessing individual break susceptibility. We also demonstrated that low-dose etoposide exposure further elevated DNA breakage at these regions in fusion-driven AML patients, but not in nonfusion patients, indicating that these sites are preferentially sensitive to TOP2 activity in fusion-driven AML patients. These results support that mapping of DSBs in patients enables discovery of novel break-prone regions and monitoring of individuals susceptible to chromosomal abnormalities, and thus cancer. This will build the foundation for early detection of cancer-susceptible individuals, as well as those preferentially susceptible to therapy-related malignancies caused by treatment with TOP2 poisons.

Relationship between coronary hyper-intensive plaques identified by cardiovascular magnetic resonance and clinical severity of acute coronary syndrome.

BACKGROUND: Coronary hyper-intense plaque (CHIP) detected on T1-weighted cardiovascular magnetic resonance (CMR) has been shown to associate with vulnerable plaque features and worse outcomes in low- and intermediate-risk populations. However, the prevalence of CHIP and its clinical significance in the higher-risk acute coronary syndrome (ACS) population have not been systematically studied. This study aims to assess the relationship between CHIP and ACS clinical severity using intracoronary optical coherence tomography (OCT) as the reference. METHODS: A total of 62 patients with known or suspected coronary artery disease were prospectively enrolled including a clinically diagnosed ACS group (n = 50) and a control group with stable angina pectoris (n = 12). The ACS group consisted of consecutive patients including unstable angina pectoris (n = 27), non-ST-segment-elevation myocardial infarction (non-STEMI) (n = 8), and ST-segment-elevation myocardial infarction (STEMI) (n = 15), respectively. All patients underwent non-contrast coronary CMR to determine the plaque-to-myocardium signal intensity ratio (PMR). RESULTS: Among the four groups of patients, a progressive increase in the prevalence of CHIPs (stable angina, 8%; unstable angina, 26%; non-STEMI, 38%; STEMI, 67%; p = 0.009), and PMR values (stable angina, 1.1; unstable angina, 1.2; non-STEMI, 1.3; STEMI, 1.6; median values, P = 0.004) were observed. Thrombus (7/8, 88% vs. 4/22, 18%, p = 0.001) and plaque rupture (5/8, 63% vs. 2/22, 9%, p = 0.007) were significantly more prevalent in CHIPs than in plaques without hyper-intensity. Elevated PMR was associated with high-risk plaque features including plaque rupture, thrombus, and intimal vasculature. A positive correlation was observed between PMR and the number of high-risk plaque features identified by OCT (r = 0.44, p = 0.015). CONCLUSIONS: The prevalence of CHIPs and PMR are positively associated with the disease severity and high-risk plaque morphology in ACS.

Generation, purification and engineering of extracellular vesicles and their biomedical applications.

Extracellular vesicles (EVs), derived from cell membranes, demonstrate the potential to be excellent therapeutics and drug carriers. Although EVs are promising, the process to develop high-quality and scalable EVs for their translation is demanding. Within this research, we analyzed the production of EVs, their purification and their post-bioengineering, and we also discussed the biomedical applications of EVs. We focus on the developments of methods in producing EVs including biological, physical, and chemical approaches. Furthermore, we discuss the challenges and the opportunities that arose when we translated EVs in clinic. With the advancements in nanotechnology and immunology, genetically engineering EVs is a new frontier in developing new therapeutics in order to tailor to individuals and different disease stages in treatments of cancer and inflammatory diseases.

Molecular Dynamics Simulations Provide Insight into the Loading Efficiency of Proresolving Lipid Mediators Resolvin D1 and D2 in Cell Membrane-Derived Nanovesicles.

Resolvins D1 and D2 (RvDs) are structural isomers and metabolites of docosahexaenoic acid, an omega-3 fatty acid, enzymatically produced in our body in response to acute inflammation or microbial invasion. Resolvins have been shown to play an essential role in the resolution of inflammation, tissue repair, and return to homeostasis and thus are actively pursued as potential therapeutics in treating inflammatory disorders and infectious diseases. However, effective in vivo delivery of RvDs continues to be a challenging task. Recent studies demonstrated that RvD1 or RvD2 loaded in cell membrane-derived nanovesicles significantly increased therapeutic efficacy in treating murine peritonitis and ischemic stroke, respectively. The mechanistic details of how the subtle structural difference between RvD1 and RvD2 alters their molecular interactions with the membrane lipids of the nanovesicles and thus affects the loading efficiency remain unknown. Here, we report the encapsulation profiles of the neutral and ionized species of both RvD1 and RvD2 determined with the cell membrane-derived nanovesicles at pH values 5.4 and 7.4, respectively. Also, we performed microsecond time-scale all-atom molecular dynamics (MD) simulations in explicit water to elucidate the molecular interactions of both neutral and ionized species of RvD1 and RvD2 with the lipid bilayer using a model membrane system, containing 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol. We found that the differences in the position and chirality of hydroxyl groups in RvD1 and RvD2 affected their location, orientation, and conformations within the bilayer. Surprisingly, the deprotonation of their carboxyl group caused their orientation and conformation to change from a fully extended one that is oriented in parallel to the membrane plane to a J-shaped bent conformation that is oriented perpendicular to the bilayer plane. Our studies offer valuable insight into the molecular interactions of RvD1/D2 with the lipid bilayer in atomistic details and provide a mechanistic explanation for the observed differences in the encapsulation profiles of RvD1 and RvD2, which may facilitate the rational design of nanovesicle-based therapeutics for treating inflammatory diseases.

Assessment of carotid atherosclerotic disease using three-dimensional cardiovascular magnetic resonance vessel wall imaging: comparison with digital subtraction angiography.

BACKGROUND: A three-dimensional (3D) cardiovascular magnetic resonance (CMR) vessel wall imaging (VWI) technique based on 3D T1 weighted (T1w) Sampling Perfection with Application-optimized Contrast using different flip angle Evolutions (SPACE) has recently been used as a promising CMR imaging modality for evaluating extra-cranial and intra-cranial vessel walls. However, this technique is yet to be validated against the current diagnostic imaging standard. We therefore aimed to evaluate the diagnostic performance of 3D CMR VWI in characterizing carotid disease using intra-arterial digital subtraction angiography (DSA) as a reference. METHODS: Consecutive patients with at least unilateral > 50% carotid stenosis on ultrasound were scheduled to undergo interventional therapy were invited to participate. The following metrics were measured using 3D CMR VWI and DSA: lumen diameter of the common carotid artery (CCA) and segments C1-C7, stenosis diameter, reference diameter, lesion length, stenosis degree, and ulceration. We assessed the diagnostic sensitivity, specificity, accuracy, and receiver operating characteristic (ROC) curve of 3D CMR VWI, and used Cohen's kappa, the intraclass correlation coefficient (ICC), and Bland-Altman analyses to assess the diagnostic agreement between 3D CMR VWI and DSA. RESULTS: The ICC (all ICCs ≥0.96) and Bland-Altman plots indicated excellent inter-reader agreement in all individual morphologic measurements by 3D CMR VWI. Excellent agreement in all individual morphologic measurements were also found between 3D CMR VWI and DSA. In addition, 3D CMR VWI had high sensitivity (98.4, 97.4, 80.0, 100.0%), specificity (100.0, 94.5, 99.1, 98.0%), and Cohen's kappa (0.99, 0.89, 0.84, 0.96) for detecting stenosis > 50%, stenosis > 70%, ulceration, and total occlusion, respectively, using DSA as the standard. The AUC of 3D CMR VWI for predicting stenosis > 50 and > 70% were 0.998 and 0.999, respectively. CONCLUSIONS: The 3D CMR VWI technique enables accurate diagnosis and luminal feature assessment of carotid artery atherosclerosis, suggesting that this imaging modality may be useful for routine imaging workups and provide comprehensive information for both the vessel wall and lumen.

Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth.

DPY30 facilitates H3K4 methylation by directly binding to ASH2L in the SET1/MLL complexes and plays an important role in hematologic malignancies. However, the domain on DPY30 that regulates cancer growth is not evident, and the potential of pharmacologically targeting this chromatin modulator to inhibit cancer has not been explored. Here we have developed a peptide-based strategy to specifically target DPY30 activity. We have designed cell-penetrating peptides derived from ASH2L that can either bind to DPY30 or show defective or enhanced binding to DPY30. The DPY30-binding peptides specifically inhibit DPY30's activity in interacting with ASH2L and enhancing H3K4 methylation. Treatment with the DPY30-binding peptides significantly inhibited the growth of MLL-rearranged leukemia and other MYC-dependent hematologic cancer cells. We also revealed subsets of genes that may mediate the effect of the peptides on cancer cell growth, and showed that the DPY30-binding peptide sensitized leukemia to other types of epigenetic inhibitors. These results strongly support a critical role of the ASH2L-binding groove of DPY30 in promoting blood cancers, and demonstrate a proof-of-principle for the feasibility of pharmacologically targeting the ASH2L-binding groove of DPY30 for potential cancer inhibition.

Nanomedicine for Ischemic Stroke.

Stroke is a severe brain disease leading to disability and death. Ischemic stroke dominates in stroke cases, and there are no effective therapies in clinic, partly due to the challenges in delivering therapeutics to ischemic sites in the brain. This review is focused on the current knowledge of pathogenesis in ischemic stroke, and its potential therapies and diagnosis. Furthermore, we present recent advances in developments of nanoparticle-based therapeutics for improved treatment of ischemic stroke using polymeric NPs, liposomes and cell-derived nanovesicles. We also address several critical questions in ischemic stroke, such as understanding how nanoparticles cross the blood brain barrier and developing in vivo imaging technologies to address this critical question. Finally, we discuss new opportunities in developing novel therapeutics by targeting activated brain endothelium and inflammatory neutrophils to improve the current therapies for ischemic stroke.

BART: a transcription factor prediction tool with query gene sets or epigenomic profiles.

Summary: Identification of functional transcription factors that regulate a given gene set is an important problem in gene regulation studies. Conventional approaches for identifying transcription factors, such as DNA sequence motif analysis, are unable to predict functional binding of specific factors and not sensitive enough to detect factors binding at distal enhancers. Here, we present binding analysis for regulation of transcription (BART), a novel computational method and software package for predicting functional transcription factors that regulate a query gene set or associate with a query genomic profile, based on more than 6000 existing ChIP-seq datasets for over 400 factors in human or mouse. This method demonstrates the advantage of utilizing publicly available data for functional genomics research. Availability and implementation: BART is implemented in Python and available at http://faculty.virginia.edu/zanglab/bart. Supplementary information: Supplementary data are available at Bioinformatics online.

Quantitative 3D dynamic contrast-enhanced (DCE) MR imaging of carotid vessel wall by fast T1 mapping using Multitasking.

PURPOSE: To develop a dynamic contrast-enhanced (DCE) MRI method capable of high spatiotemporal resolution, 3D carotid coverage, and T1-based quantification of contrast agent concentration for the assessment of carotid atherosclerosis using a newly developed Multitasking technique. METHODS: 5D imaging with 3 spatial dimensions, 1 T1 recovery dimension, and 1 DCE time dimension was performed using MR Multitasking based on low-rank tensor modeling, which allows direct T1 quantification with high spatiotemporal resolution (0.7 mm isotropic and 595 ms, respectively). Saturation recovery preparations followed by 3D segmented fast low angle shot readouts were implemented with Gaussian-density random 3D Cartesian sampling. A bulk motion removal scheme was developed to improve image quality. The proposed protocol was tested in phantom and human studies. In vivo scans were performed on 14 healthy subjects and 7 patients with carotid atherosclerosis. Kinetic parameters including area under the concentration versus time curve (AUC), vp , Ktrans , and ve were evaluated for each case. RESULTS: Phantom experiments showed that T1 measurements using the proposed protocol were in good agreement with reference value ( R2=0.96 ). In vivo studies demonstrated that AUC, vp , and Ktrans in the patient group were significantly higher than in the control group (0.63 ± 0.13 versus 0.42 ± 0.12, P < 0.001; 0.14 ± 0.05 versus 0.11 ± 0.03, P = 0.034; and 0.13 ± 0.04 versus 0.08 ± 0.02, P < 0.001, respectively). Results from repeated subjects showed good interscan reproducibility (intraclass correlation coefficient: vp , 0.83; Ktrans , 0.87; ve , 0.92; AUC, 0.94). CONCLUSION: Multitasking DCE is a promising approach for quantitatively assessing the vascularity properties of the carotid vessel wall.

Association between serum/plasma levels of adiponectin and obstructive sleep apnea hypopnea syndrome: a meta-analysis.

BACKGROUND: The relationship between obstructive sleep apnea hypopnea syndrome (OSAHS) and a variety of disease from obesity, type 2 diabetes mellitus and cardiovascular disease has been investigated previously. Reduced adiponectin levels are also associated with increased risk of these disease. However, whether serum/plasma adiponectin levels in OSAHS patients are lower than their counterparts remain controversial. Therefore, this study evaluated the association between serum/plasma adiponectin levels and OSAHS. METHODS: We performed a comprehensive literature search to locate eligible articles published on electronic databases including PubMed, EMBASE, Cochrane Library, WANFANG (Chinese database), VIP (Chinese Database) and Chinese National Knowledge Infrastructure (CNKI). The methodological quality of included studies was evaluated using the Newcastle-Ottawa scale (NOS). Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated as effect size. Heterogeneity test was performed by Cochrane Q test and I2 test. Subgroup analysis and meta-regression analysis were employed to detect the sources of the heterogeneity. RevMan 5.3 and Stata 12.0 software were used in this meta-analysis for data synthesis. RESULTS: A total of 20 eligible studies with 28 databases involving 1356 participants were included in this meta-analysis. Results revealed that serum/plasma adiponectin levels in OSAHS patients were significantly lower than that in controls [SMD = - 0.71, 95% CI = - 0.92 to - 0.49, p < 0.001]. Subgroup analysis indicated that the heterogeneity would decreased when subgroup analysis was stratified by race. In addition, meta-regression analysis also suggested that the adiponectin levels were only significantly correlated with race. The removal of any independent study did not affect the pooled SMD in the sensitivity analysis. CONCLUSION: The serum/plasma adiponectin levels were significantly lower in OSAHS patients than that in control subjects, suggesting a possible role of adiponectin in OSAHS pathogenesis, deserves further studies as a potential marker of OSAHS.

Atherosclerosis T1-weighted characterization (CATCH): evaluation of the accuracy for identifying intraplaque hemorrhage with histological validation in carotid and coronary artery specimens.

BACKGROUND: Coronary high intensity plaques (CHIPs) detected using cardiovascular magnetic resonance (CMR) coronary atherosclerosis T1-weighted characterization with integrated anatomical reference (CATCH) have been shown to be positively associated with high-risk morphology observed on intracoronary optical coherence tomography (OCT). This study sought to validate whether CHIPs detected on CATCH indicate the presence of intraplaque hemorrhage (IPH) through ex vivo imaging of carotid and coronary plaque specimens, with histopathology as the standard reference. METHODS: Ten patients scheduled to undergo carotid endarterectomy underwent CMR with the conventional T1-weighted (T1w) sequence. Eleven carotid atherosclerotic plaques removed at carotid endarterectomy and six coronary artery endarterectomy specimens removed from patients undergoing coronary artery bypass grafting (CABG) were scanned ex vivo using both the conventional T1w sequence and CATCH. Both in vivo and ex vivo images were examined for the presence of IPH. The sensitivity, specificity, and Cohen Kappa (k) value of each scan were calculated using matched histological sections as the reference. k value between each scan in the discrimination of IPH was also computed. RESULTS: A total of 236 in vivo locations, 328 ex vivo and matching histology locations were included for the analysis. Sensitivity, specificity, and k value were 76.7%, 95.3%, and 0.75 for in vivo T1w imaging, 77.2%, 97.4%, and 0.78 for ex vivo T1w imaging, and 95.0%, 92.1%, and 0.84 for ex vivo CATCH, respectively. Moderate agreement was reached between in vivo T1w imaging, ex vivo T1w imaging, and ex vivo CATCH for the detection of IPH: between in vivo T1w imaging and ex vivo CATCH (k = 0.68), between ex vivo T1w imaging and ex vivo CATCH (k = 0.74), between in vivo T1w imaging and ex vivo T1w imaging (k = 0.83). None of the coronary artery plaque locations showed IPH. CONCLUSION: This study demonstrated that carotid CHIPs detected by CATCH can be used to assess for IPH, a high-risk plaque feature.

DARDN: A Deep-Learning Approach for CTCF Binding Sequence Classification and Oncogenic Regulatory Feature Discovery.

Characterization of gene regulatory mechanisms in cancer is a key task in cancer genomics. CCCTC-binding factor (CTCF), a DNA binding protein, exhibits specific binding patterns in the genome of cancer cells and has a non-canonical function to facilitate oncogenic transcription programs by cooperating with transcription factors bound at flanking distal regions. Identification of DNA sequence features from a broad genomic region that distinguish cancer-specific CTCF binding sites from regular CTCF binding sites can help find oncogenic transcription factors in a cancer type. However, the presence of long DNA sequences without localization information makes it difficult to perform conventional motif analysis. Here, we present DNAResDualNet (DARDN), a computational method that utilizes convolutional neural networks (CNNs) for predicting cancer-specific CTCF binding sites from long DNA sequences and employs DeepLIFT, a method for interpretability of deep learning models that explains the model's output in terms of the contributions of its input features. The method is used for identifying DNA sequence features associated with cancer-specific CTCF binding. Evaluation on DNA sequences associated with CTCF binding sites in T-cell acute lymphoblastic leukemia (T-ALL) and other cancer types demonstrates DARDN's ability in classifying DNA sequences surrounding cancer-specific CTCF binding from control constitutive CTCF binding and identifying sequence motifs for transcription factors potentially active in each specific cancer type. We identify potential oncogenic transcription factors in T-ALL, acute myeloid leukemia (AML), breast cancer (BRCA), colorectal cancer (CRC), lung adenocarcinoma (LUAD), and prostate cancer (PRAD). Our work demonstrates the power of advanced machine learning and feature discovery approach in finding biologically meaningful information from complex high-throughput sequencing data.

Integrative analysis of DNA replication origins and ORC-/MCM-binding sites in human cells reveals a lack of overlap.

Based on experimentally determined average inter-origin distances of ~100 kb, DNA replication initiates from ~50,000 origins on human chromosomes in each cell cycle. The origins are believed to be specified by binding of factors like the origin recognition complex (ORC) or CTCF or other features like G-quadruplexes. We have performed an integrative analysis of 113 genome-wide human origin profiles (from five different techniques) and five ORC-binding profiles to critically evaluate whether the most reproducible origins are specified by these features. Out of ~7.5 million union origins identified by all datasets, only 0.27% (20,250 shared origins) were reproducibly obtained in at least 20 independent SNS-seq datasets and contained in initiation zones identified by each of three other techniques, suggesting extensive variability in origin usage and identification. Also, 21% of the shared origins overlap with transcriptional promoters, posing a conundrum. Although the shared origins overlap more than union origins with constitutive CTCF-binding sites, G-quadruplex sites, and activating histone marks, these overlaps are comparable or less than that of known transcription start sites, so that these features could be enriched in origins because of the overlap of origins with epigenetically open, promoter-like sequences. Only 6.4% of the 20,250 shared origins were within 1 kb from any of the ~13,000 reproducible ORC-binding sites in human cancer cells, and only 4.5% were within 1 kb of the ~11,000 union MCM2-7-binding sites in contrast to the nearly 100% overlap in the two comparisons in the yeast, Saccharomyces cerevisiae. Thus, in human cancer cell lines, replication origins appear to be specified by highly variable stochastic events dependent on the high epigenetic accessibility around promoters, without extensive overlap between the most reproducible origins and currently known ORC- or MCM-binding sites.

In-situ formed Co nano-clusters as separator modifier and catalyst to regulate the film-like growth of Li and promote the cycling stability of lithium metal batteries.

Lithium metal batteries (LMBs) are considered a highly prospective next-generation energy storage technology. However, their large-scale commercial application is hampered by the uncontrollable growth of Li dendrites, which accompany the boundless inflation of the battery's volume. In this study, we address this challenge by fabricating a porous structure of the MOF-derived CoP nanocube film (CoP-NC@PP) as a adorned layer for the separator. During the initial cycle, this film facilitates the in situ formation of Li3P with ultrahigh ionic conductivity and a lithiophilic Co, which helps rule the nucleation and deposition behavior of lithium and stabilizes the solid-electrolyte interphase. The symmetric cell incorporating the CoP-NC@PP modified layer exhibits exceptional cycling stability, surpassing 1500 h of continuous operation. The kinetic process of Li interaction with CoP and the structural factors contributing to the high cycling stability and high naminal voltage were investigated by molecular dynamics simulation and density functional theory calculations. Furthermore, full cells employing Li||CoP-NC@PP||LFP (LFP = LiFePO4) configurations demonstrate excellent cycling stability and high capacity, even at a high rate of 5 C (≈5.2 mA cm-2), with the cathode mass loading reaching as high as 10.3 mg cm-2.