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The same types of cells can assume diverse states with varying functionalities. Effective cell therapy can be achieved by specifically driving a desirable cell state, which requires the elucidation of key transcription factors (TFs). Here, we integrated epigenomic and transcriptomic data at the systems level to identify TFs that define different CD8+T cell states in an unbiased manner. These TF profiles can be used for cell state programming that aims to maximize the therapeutic potential of T cells. For example, T cells can be programmed to avoid a terminal exhaustion state (TexTerm), a dysfunctional T cell state that is often found in tumors or chronic infections. However, TexTermexhibits high similarity with the beneficial tissue-resident memory T states (TRM) in terms of their locations and transcription profiles. Our bioinformatic analysis predictedZscan20, a novel TF, to be uniquely active in TexTerm. Consistently,Zscan20knock-out thwarted the differentiation of TexTermin vivo, but not that of TRM. Furthermore, perturbation ofZscan20programs T cells into an effector-like state that confers superior tumor and virus control and synergizes with immune checkpoint therapy. We also identifiedJdp2andNfil3as powerful TexTermdrivers. In short, our multiomics-based approach discovered novel TFs that enhance anti-tumor immunity, and enable highly effective cell state programming.One sentence summaryMultiomics atlas enables the systematic identification of cell-state specifying transcription factors for therapeutic cell state programming.

Hyperspectral images have a special attribute with both spectral and spatial information, which is of great significance for the evaluation of the stealth performance of camouflaged targets. Aiming at the problems of a single evaluation index and the low credibility of traditional optical camouflage evaluation methods, this paper proposes a grayscale clustering camouflage effect evaluation method based on multifeature descriptions of hyperspectral images using similarity indicators that reflect different spectral characteristics of the target and background. From the perspective of spectrum and human visual contrast, a comprehensive evaluation index system including spectral distance feature, spectral derivative feature, curve shape feature and spatial texture feature is constructed by combining spatial–spectral multi-feature constraints. At the same time, an improved Delphi method is proposed to simulate the expert decision-making process, and better evaluation weights are obtained by comparison and screening. The comprehensive evaluation of camouflage effect based on whitening function gray clustering is realized. The proposed method can not only give the “excellent” and “bad” of camouflage effect qualitatively, but also calculate the comprehensive score of camouflage effect by model.

SummaryThe limited efficacy of immunotherapies against glioblastoma illustrates the urgent need to better understand the interactions between the central nervous system and the immune system. Here, we showed that a protective response to αCTLA-4 therapy depended on a mutualistic relationship between microglia and CD4+ T cells. Suppression of gliomas by CD4+ T cells did not require tumor-intrinsic MHC-II expression, but rather was dependent on the selective expression of MHC-II and antigen presentation by local microglia that in turn, sustained CD4+ T cell tumoricidal effector functions. CD4+ T cell secretion of IFNγ made the glioma cells vulnerable to enhanced tumor surveillance and phagocytosis by microglia via the AXL/MER tyrosine kinase receptors that were necessary for tumor suppression. This work illustrates a novel partnership between CD4+ T cells and microglia that unleashes the tumoricidal properties of microglia that can be harnessed to improve immunotherapies for glioblastoma.

Robust and effective small-target detection in infrared (IR) imagery has significant implications for modern military operations. For the objective of achieving simultaneous solid performance in detection rate, false alarm rate (FAR), and speed, this research provides a novel method making use of local contrast measure (LCM) based on high-boost filters [novel high-boost filter improved LCM (NHBF-ILCM)]. First, a novel high-boost filter is used for target signal enhancement and background clutter suppression, followed by an ILCM used to achieve high-speed local contrast and further target resolution enhancement and clutter suppression. Then, an adaptive threshold is used to segment the target. Finally, through experiments using three sequences with different and typically complex backgrounds, the detection capabilities of the proposed method are confirmed, and these results reveal that the proposed algorithm is able to achieve the best performance and highest efficiency for real IR small-target detection applications among similar algorithms.

SUMMARYCRISPR-Cas13 systems have been adapted as versatile toolkits for RNA-related applications. Here we systematically evaluate the performance of several popular Cas13 family effectors (Cas13a, Cas13b and Cas13d) under lentiviral vectors and reveal surprisingly differential defects and characteristics of these systems. Using RNA immunoprecipitation sequencing, transcriptome profiling, biochemistry analysis, high-throughput CRISPR-Cas13 screening and machine learning approaches, we determine that each Cas13 system has its intrinsic RNA targets in mammalian cells. Viral process-related host genes can be targeted by Cas13 and affect production of fertile lentiviral particles, thereby restricting the utility of lentiviral Cas13 systems. Multiple RNase activities of Cas13 are involved in endogenous RNA targeting. Unlike target-induced nonspecific collateral effect, intrinsic RNA cleavage can be specific, target-independent and dynamically tuned by varied states of Cas13 nucleases. Our work provides guidance on appropriate use of lentiviral Cas13 systems and further raises cautions about intrinsic RNA targeting during Cas13-based basic and therapeutic applications.

Despite the fundamental roles of TGF-β family signaling in cell fate determination in all metazoans, the mechanism by which these signals are spatially and temporally interpreted remains elusive. The cell-context-dependent function of TGF-β signaling largely relies on transcriptional regulation by SMAD proteins. Here, we discover that the DNA repair-related protein, HMCES, contributes to early development by maintaining nodal/activin- or BMP-signaling-regulated transcriptional network. HMCES binds with R-SMAD proteins, co-localizing at active histone marks. However, HMCES chromatin occupancy is independent on nodal/activin or BMP signaling. Mechanistically, HMCES competitively binds chromatin to limit binding by R-SMAD proteins, thereby forcing their dissociation and resulting in repression of their regulatory effects. In Xenopus laevis embryo, hmces KD causes dramatic development defects with abnormal left-right axis asymmetry along with increasing expression of lefty1. These findings reveal HMCES transcriptional regulatory function in the context of TGF-β family signaling.

Objective : This study focused on developing a fast and accurate automatic ischemic heart disease detection/localization methodology. Methods: T wave was segmented from averaged Magnetocardiography (MCG) recordings and 164 features were subsequently extracted. These features were categorized into three groups: time domain features, frequency domain features, and information theory features. Next, we compared different machine learning classifiers including: k-nearest neighbor, decision tree, support vector machine (SVM), and XGBoost. To identify ischemia heart disease (IHD) case, we selected three classifiers with best performance and applied model ensemble to average results. All 164 features were used in this stage. To localize ischemia, we classified IHD group according to stenosis locations, including left anterior descending (LAD), left circumflex artery (LCX), and right coronary artery (RCA). For this task, we used XGBoost classifier and 18 time domain features. Results: For IHD detection, the SVM-XGBoost model achieved best results with accuracy = 94.03%, precision = 86.56%, recall = 97.78%, F-score = 92.79%, AUC = 0.98, and average precision = 0.98. For ischemia localization, XGBoost model achieved accuracy = 0.74, 0.68, and 0.65, for LAD, LCX, and RCA, respectively. Conclusion: we have developed an automatic IHD detection and localization system. We find that 1. T wave repolarization synchronicity is an important factor to distinguish IHD from normal subjects 2. Magnetic field pattern is associated with stenosis location. Significance: The proposed machine learning method provides the clinicians a fast and accurate diagnosis tool to interpret MCG data, boosting its acceptance into clinics. Furthermore, the magnetic pole characteristics revealed by the method shows to be related to ischemia location, presenting the opportunity to noninvasively locate ischemia.

Deep learning-based SAR target classification has gained great success recently. However, the machine learning models are vulnerable to adversarial attacks which may cause severe security issue. In this paper, a convolution neural network (CNN)-based SAR target classification model is trained and used to perform the universal perturbation attack. We find out that the SAR target classification model is also vulnerable to universal adversarial attacks. By adding an image-agnostic and very small perturbation, the classification accuracy deteriorates a lot.

In the direct competition for metabolic resources between cancer cells and tumor-infiltrating CD8+ T cells, the latter are bound to lose out. These effector lymphocytes are therefore rendered exhausted or dysfunctional. Emerging insights into the mechanisms of T cell unresponsiveness in the tumor microenvironment (TME) point towards epigenetic mechanisms as crucial regulatory factors. In this review, we discuss the effects of characteristic components of the TME, i.e. glucose/amino acid dearth with elevated levels of reactive oxygen species (ROS), on DNA methylation and histone modifications in CD8+ T cells. We then take a closer look at the translational potential of epigenetic interventions that aim to improve current immunotherapeutic strategies, including the adoptive transfer of T cell receptor (TCR) or chimeric antigen receptor (CAR) engineered T cells. ispartof: TRENDS IN IMMUNOLOGY vol:42 issue:5 pages:401-417 ispartof: location:England status: published

Summary RNA viruses are responsible for many zoonotic diseases that post great challenges for public health. Effective therapeutics against these viral infections remain limited. Here, we deployed a computational framework for host-based drug repositioning to predict potential antiviral drugs from 2,352 approved drugs and 1,062 natural compounds embedded in herbs of traditional Chinese medicine. By systematically interrogating public genetic screening data, we comprehensively cataloged host dependency genes (HDGs) that are indispensable for successful viral infection corresponding to 10 families and 29 species of RNA viruses. We then utilized these HDGs as potential drug targets and interrogated extensive drug-target interactions through database retrieval, literature mining, and de novo prediction using artificial intelligence-based algorithms. Repurposed drugs or natural compounds were proposed against many viral pathogens such as coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses, and influenza viruses. This study helps to prioritize promising drug candidates for in-depth evaluation against these virus-related diseases., Graphical abstract, Highlights • Host dependency genes for RNA viruses are systematically cataloged • Repositioned drug candidates target host dependency genes for antiviral purpose • Artificial intelligence-based algorithms help to predict drug-target interactions • Prioritized antiviral drug candidates are proposed against RNA viruses, Molecular Biology; Bioinformatics; Pharmacoinformatics

RNA viruses are responsible for many types of zoonotic diseases that post great challenges for public health system. Effective therapeutics against these viral infections remains limited. Here we deployed a computational framework for host-based drug repositioning to predict potential antiviral drug candidates from 2352 approved drugs and 1062 natural compounds embedded in Traditional Chinese Medicine herbs. By systematically interrogating public genetic screening data, we comprehensively catalogued human-specific host dependency genes that are indispensable for the successful viral infection corresponding to 10 families and 29 species of RNA viruses. In addition, we utilized these host dependency genes as potential drug targets, and interrogated extensive drug-target interactions through multiple ways such as database retrieval, literature mining and de novo prediction using artificial intelligence-based algorithms. Repurposed drugs or natural compounds were proposed for combating many viral pathogens such as coronaviruses (e.g., SARS-CoV-2), flaviviruses (e.g., Zika virus) and influenza viruses. This study helps to prioritize promising drug candidates for further therapeutic evaluation against these viral-related diseases.

Background/Aims: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if SIRT1 alleviates CRS through ER stress reduction. Methods: Wild type mice (n=37), mice with cardiac-specific SIRT1 knockout (n=29), or overexpression (n=29), and corresponding controls, were randomized into four groups: sham MI (myocardial infarction) +sham STNx (subtotal nephrectomy); MI+sham STNx; sham MI+STNx; and MI+STNx. To establish the CRS model, subtotal nephrectomy (5/6 nephrectomy, SNTx) and myocardial infarction (MI) (induced by ligation of the left anterior descending (LAD) coronary artery) were performed successively to establish CRS model. At week 8, the mice were sacrificed after sequential echocardiographic and hemodynamic studies, and then pathology and Western-blot analysis were performed. Results: Neither MI nor STNx alone significantly influenced the other healthy organ. However, in MI groups, STNx led to more severe cardiac structural and functional deterioration, with increased remodeling, increased BNP levels, and decreased EF, Max +dp/dt, and Max -dp/dt values than in sham MI +STNx groups. Conversely, in STNx groups, MI led to renal structural and functional deterioration, with more severe morphologic changes, augmented desmin and decreased nephrin expression, and increased BUN, SCr and UCAR levels. In MI+STNx groups, SIRT1 knockout led to more severe cardiac structural and functional deterioration, with higher Masson-staining score and BNP levels, and lower EF, FS, Max +dp/dt, and Max -dp/dt values; while SIRT1 overexpression had the opposite attenuating effects. In kidney, SIRT1 knockout resulted in greater structural and functional deterioration, as evidenced by more severe morphologic changes, higher levels of UACR, BUN and SCr, and increased desmin and TGF-β expression, while SIRT1 overexpression resulted in less severe morphologic changes and increased nephrin expression without significant influence on BUN or SCr levels. The SIRT1 knockout but not overexpression resulted in increased myocardial expression of CHOP and GRP78. Cardiac-specific SIRT1 knockout or overexpression resulted in increased or decreased renal expression of CHOP, Bax, and p53 respectively. Conclusions: Myocardial SIRT1 activation appears protective to both heart and kidney in CRS models, probably through modulation of ER stress.

The CRISPR-based nucleic acid detection systems have shown great potential for point-of-care testing of viral pathogens, especially in the context of COVID-19 pandemic. Here we optimize several key parameters of reaction chemistry and develop a Chemical Enhanced CRISPR Detection system for nucleic acid (termed CECRID). For the Cas12a/Cas13a-based signal detection phase, we determine buffer conditions and substrate range for optimal detection performance, and reveal a crucial role of bovine serum albumin in enhancing trans-cleavage activity of Cas12a/Cas13a effectors. By comparing several chemical additives, we find that addition of L-proline can secure or enhance Cas12a/Cas13a detection capability. For isothermal amplification phase with typical LAMP and RPA methods, inclusion of L-proline can also enhance specific target amplification as determined by CRISPR detection. Using SARS-CoV-2 pseudovirus, we demonstrate CECRID has enhanced detection sensitivity over chemical additive-null method with either fluorescence or lateral flow strip readout. Thus, CECRID provides an improved detection power and system robustness, and helps to develop enhanced reagent formula or test kit towards practical application of CRISPR-based diagnostics.

This study investigated roles of serum ST2, IL‐33 and BNP in predicting major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Blood samples were collected from the included AMI patients (n = 180) who underwent PCI. All patients were divided into the MACEs and MACEs‐free groups. Enzyme‐linked immunosorbent assay was performed to measure serum levels of ST2, IL‐33 and BNP. Severity of coronary artery lesion was evaluated by Gensini score. Pearson correlation analysis was used. A receiver operating characteristics curve was drawn to evaluate the potential roles of ST2, IL‐33 and BNP in predicting MACEs, and Kaplan–Meier curve to analyse the 1‐year overall survival rate. Logistic regression analysis was conducted to analyse the independent risk factors for MACEs. Compared with the MACEs‐free group, the serum levels of ST2, IL‐33 and BNP were significantly higher in the MACEs group. Serum levels of ST2, IL‐33 and BNP were positively correlated with each other and positively correlated with Gensini score. The area under curves of ST2, IL‐33 and BNP, respectively, were 0.872, 0.675 and 0.902. The relative sensitivity and specificity were, respectively, 76.27% and 85.92%, 69.49% and 58.68%, as well as, 96.61% and 77.69%. Serum levels of ST2, IL‐33 and BNP were independent risk factors for MACEs. The 1‐year overall survival rate was higher in AMI patients with lower serum levels of ST2, IL‐33 and BNP. In conclusion, serum levels of ST2, IL‐33 and BNP have potential value in predicting MACEs in AMI patients undergoing PCI.

Marine zooplankton has important ecological and economic value. The observation and automatic image recognition technology of marine zooplankton is an important mean to acquire data such as species, quantity, spatial distribution and behavioral postures of zooplankton, and is an important support for marine scientific research. Digital holography has an innate advantage of refocusing and reconstruction, which is suitable for deep learning and living zooplankton recognition. In this study, a large number of holographic images was trained by using the improved YOLOv2 model, and after test, the study achieved satisfactory results: the models trained by the images with sharpness assessment score of 0.6 or higher, have precision rate above 94% and a recall rate above 88%. This study mainly discusses: (1) the detection method of moving targets to acquire the images of moving zooplankton; (2) the two factors that affect the holographic images recognition results, mean (pixel mean of images) subtraction operation and image sharpness, and the no-reference sharpness assessment based on structural similarity for holographic images; (3) the relationship between sharpness assessment index or mean subtraction and the recognition results.

Our knowledge of T cell metabolism relies primarily on studies performed in vitro that may not fully recapitulate physiological conditions in vivo. In this issue of Immunity, Ma et al. find that the in vivo environment dictates the metabolic phenotype of effector CD8+ T cells—particularly their glucose utilization.

Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic–epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC development but led to pronounced reduction in naïve and memory–phenotype cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification., Dendritic cells (DCs) play pivotal roles in T cell homeostasis and activation, but the basis of the metabolic programming of distinct DC functions remains unclear. This study identifies a novel metabolic-epigenetic node enabling DC control of CD8 T cell homeostasis, involving mTOR-ACC1 as a rheostat that balances fatty-acid synthesis and histone acetylation.

Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called 'Shp-2' here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1β (IL-1β), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection.

Background The Cappella Sideguard (CS) sidebranch stent is a self-expanding, thin-strut, nitinol device with anatomic flaring at the sidebranch ostium designed to treat bifurcation lesions. Objective To evaluate the mechanism of long-term lumen patency of the novel, self-expanding CS sidebranch stent compared with a balloon-expandable stent in the main vessel. Methods We performed intravascular ultrasound postintervention and at follow-up in 24 CS stents and in 28 balloon-expandable drug-eluting stents deployed in the corresponding main vessel. Thirteen patients also had optical coherence tomography (OCT) at follow-up to evaluate neointimal hyperplasia and strut coverage. Results CS stent area at the sidebranch carina increased significantly from 3.8 ± 1.2 mm2 postintervention to 4.6 ± 1.2 mm2 at follow-up (P

Objectives We compared the mechanisms of lumen gain after Cappella Sideguard (CS) side branch (SB) bifurcation stent deployment versus a balloon-expandable stent in the corresponding main vessel (MV). Background The novel CS SB bifurcation stent is a self-expanding, thin-strut, nitinol device with anatomic flaring at the SB ostium. Methods In 28 bifurcation lesions, intravascular ultrasound imaging of both the SB and the MV was performed both pre- and postintervention; vessel and lumen areas were measured every 1 mm over a 5 mm segment beginning at the carina. Results Although minimum lumen area (MLA) within the distal 5 mm segment beginning at the carina increased from 2.8 ± 1.3 mm2 to 3.8 ± 1.1 mm2, P

The purpose of this study was to determine whether use of iterative image reconstruction algorithms improves the accuracy of coronary CT angiography (CCTA) compared with intravascular ultrasound (IVUS) in semiautomated plaque burden assessment.CCTA and IVUS images of seven coronary arteries were acquired ex vivo. CT images were reconstructed with filtered back projection (FBP) and adaptive statistical (ASIR) and model-based (MBIR) iterative reconstruction algorithms. Cross-sectional images of the arteries were coregistered between CCTA and IVUS in 1-mm increments. In CCTA, fully automated (without manual corrections) and semiautomated (allowing manual corrections of vessel wall boundaries) plaque burden assessments were performed for each of the reconstruction algorithms with commercially available software. In IVUS, plaque burden was measured manually. Agreement between CCTA and IVUS was determined with Pearson correlation.A total of 173 corresponding cross sections were included. The mean plaque burden measured with IVUS was 63.39% ± 10.63%. With CCTA and the fully automated technique, it was 54.90% ± 11.70% with FBP, 53.34% ± 13.11% with ASIR, and 55.35% ± 12.22% with MBIR. With CCTA and the semiautomated technique mean plaque burden was 54.90% ± 11.76%, 53.40% ± 12.85%, 57.09% ± 11.05%. Manual correction of the semiautomated assessments was performed in 39% of all cross sections and improved plaque burden correlation with the IVUS assessment independently of reconstruction algorithm (p0.0001). Furthermore, MBIR was superior to FBP and ASIR independently of assessment method (semiautomated, r = 0.59 for FBP, r = 0.52 for ASIR, r = 0.78 for MBIR, all p0.001; fully automated, r = 0.40 for FBP, r = 0.37 for ASIR, r = 0.53 for MBIR, all p0.001).For the quantification of plaque burden with CCTA, MBIR led to better correlation with IVUS than did traditional reconstruction algorithms such as FBP, independently of the use of a fully automated or semiautomated assessment approach. The highest accuracy for quantifying plaque burden with CCTA can be achieved by using MBIR data with semiautomated assessment.

Ma and colleagues identify CXXC5 as an epigenetic regulator required for maintaining the hypomethylation of a subset of CGIs, thereby promoting the expression of transcriptional factors such as IRF7 in pDCs to enable robust IFN response to viral infection., TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs. Mechanistically, CXXC5 is responsible for the recruitment of DNA demethylase Tet2 to maintain the hypomethylation of a subset of CGIs, a process coincident with active histone modifications and constitutive transcription of these CGI-containing genes. Consequently, CXXC5-deficient mice had compromised early IFN response and became highly vulnerable to infection by herpes simplex virus and vesicular stomatitis virus. Together, our results identify CXXC5 as a novel epigenetic regulator for pDC-mediated antiviral response.

To establish an ex vivo experimental setup for imaging coronary atherosclerosis with coronary computed tomographic (CT) angiography, intravascular ultrasonography (US), and optical frequency domain imaging (OFDI) and to investigate their ability to help differentiate early from advanced coronary plaques.All procedures were performed in accordance with local and federal regulations and the Declaration of Helsinki. Approval of the local Ethics Committee was obtained. Overall, 379 histologic cuts from nine coronary arteries from three donor hearts were acquired, coregistered among modalities, and assessed for the presence and composition of atherosclerotic plaque. To assess the discriminatory capacity of the different modalities in the detection of advanced lesions, c statistic analysis was used. Interobserver agreement was assessed with the Cohen κ statistic.Cross sections without plaque at coronary CT angiography and with fibrous plaque at OFDI almost never showed advanced lesions at histopathologic examination (odds ratio [OR]: 0.02 and 0.06, respectively; both P.0001), while mixed plaque at coronary CT angiography, calcified plaque at intravascular US, and lipid-rich plaque at OFDI were associated with advanced lesions (OR: 2.49, P=.0003; OR: 2.60, P=.002; and OR: 31.2, P.0001, respectively). OFDI had higher accuracy for discriminating early from advanced lesions than intravascular US and coronary CT angiography (area under the receiver operating characteristic curve: 0.858 [95% confidence interval {CI}: 0.802, 0.913], 0.631 [95% CI: 0.554, 0.709], and 0.679 [95% CI: 0.618, 0.740]; respectively, P.0001). Interobserver agreement was excellent for OFDI and coronary CT angiography (κ=0.87 and 0.85, respectively) and was good for intravascular US (κ=0.66).Systematic and standardized comparison between invasive and noninvasive modalities for coronary plaque characterization in ex vivo specimens demonstrated that coronary CT angiography and intravascular US are reasonably associated with plaque composition and lesion grading according to histopathologic findings, while OFDI was strongly associated. These data may help to develop initial concepts of sequential imaging strategies to identify patients with advanced coronary plaques.

To systematically assess inter-technique and inter-/intra-reader variability of coronary CT angiography (CTA) to measure plaque burden compared with intravascular ultrasound (IVUS) and to determine whether iterative reconstruction algorithms affect variability.IVUS and CTA data were acquired from nine human coronary arteries ex vivo. CT images were reconstructed using filtered back projection (FBPR) and iterative reconstruction algorithms: adaptive-statistical (ASIR) and model-based (MBIR). After co-registration of 284 cross-sections between IVUS and CTA, two readers manually delineated the cross-sectional plaque area in all images presented in random order.Average plaque burden by IVUS was 63.7 ± 10.7% and correlated significantly with all CTA measurements (r = 0.45-0.52; P 0.001), while CTA overestimated the burden by 10 ± 10%. There were no significant differences among FBPR, ASIR and MBIR (P 0.05). Increased overestimation was associated with smaller plaques, eccentricity and calcification (P 0.001). Reproducibility of plaque burden by CTA and IVUS datasets was excellent with a low mean intra-/inter-reader variability of1/4% for CTA and0.5/1% for IVUS respectively (P 0.05) with no significant difference between CT reconstruction algorithms (P 0.05).In ex vivo coronary arteries, plaque burden by coronary CTA had extremely low inter-/intra-reader variability and correlated significantly with IVUS measurements. Accuracy as well as reader reliability were independent of CT image reconstruction algorithm.• IVUS is deemed the gold standard in-vivo coronary plaque assessment • But coronary CT angiography findings correlate strongly with IVUS results • Coronary CT angiography now allows plaque quantification close to IVUS • Iterative image reconstruction algorithms do not alter accuracy or reproducibility • Plaque quantification is more challenging in smaller eccentric calcified lesions.

TLR7/9 signals are capable of mounting massive IFN response in pDCs immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Through immune gene profiling, we found that the zinc finger CXXC family epigenetic regulator CXXC5 is specifically expressed in pDCs, but not in cDCs or macrophages. Interestingly, CXXC5-deficient pDCs exhibited impaired IFN-I response to TLR7/9 ligands and RNA/DNA viruses. Furthermore, we uncovered that CXXC5-deficiency resulted in aberrant methylation of CpG DNA islands (CGIs) of a subset of genes including Irf7 in the steady-state pDCs, leading to diminished expression of this group of genes in pDCs. Mechanistically, CXXC5 seemed to be responsible for the recruitment of DNA demethylase Tet2 to maintain the hypomethylation of these CGIs in pDCs, a process coincided with histone remodeling and active transcription in these regions. Upon challenged by viruses, CXXC5-deficient mice were unable to launch robust IFN-I response at the early stage, and became highly susceptible to HSV and VSV infection. Together, our results not only identified CXXC5 as a novel regulator of TLR7/9-induced IFN-I response in host defense, but also provided new insight into the understanding of epigenetic regulation of pDC function.

ADP plays an important part in platelet aggregation by activating P2Y1 and P2Y12 receptors. The ADP antagonist MRS2179 has been used in thrombosis-related treatments but its effects on vein graft (VG) remodeling is undefined. We examined the effect of MRS2179 on VG intimal hyperplasia and explored the mechanism of action. A mouse model of VG transplantation was established. Mice underwent surgery and received MRS2179 by intraperitoneal injection every other day for 3 weeks. VG remodeling was assessed 4-weeks later. Vascular smooth muscle cells (VSMCs) were isolated and treated with MRS2179. The effect of MRS2179 on the proliferation, migration and inflammatory-cytokine expression of VSMCs was also evaluated. MRS2179 significantly inhibited VSMC proliferation compared with the control group. Significant inhibitory effects of MRS2179 on VSMC migration was observed in two-dimensional and three-dimensional models. The extent of intimal hyperplasia was significantly less in MRS2179 treated mice than in controls. Reduced migration of macrophage was found in MRS2179 treated mice. Expression of the inflammatory cytokines IL-1β and TNF-α was decreased significantly in the MRS2179 treated group. In addition, decreased phosphorylation was found on Akt, Erk1/2 and p38. These data demonstrate that MRS2179 inhibits neointima formation in VGs by regulating the proliferation, and migration of VSMCs, macrophage migration, inflammatory-cytokine secretion and related signaling pathway. Our study provides novel insights regarding purinergic signaling in SMCs in vivo. The P2Y1 receptor may serve as a therapeutic target in neointima formation.

The Cappella Sideguard (CS) sidebranch stent is a self-expanding, thin-strut, nitinol device with anatomic flaring at the sidebranch ostium designed to treat bifurcation lesions.To evaluate the mechanism of long-term lumen patency of the novel, self-expanding CS sidebranch stent compared with a balloon-expandable stent in the main vessel.We performed intravascular ultrasound postintervention and at follow-up in 24 CS stents and in 28 balloon-expandable drug-eluting stents deployed in the corresponding main vessel. Thirteen patients also had optical coherence tomography (OCT) at follow-up to evaluate neointimal hyperplasia and strut coverage.CS stent area at the sidebranch carina increased significantly from 3.8 ± 1.2 mm(2) postintervention to 4.6 ± 1.2 mm(2) at follow-up (P0.001), resulting in no change in lumen area (3.8 ± 1.2 mm(2) to 3.7 ± 1.2 mm(2) , P = 0.72) despite a neointimal area at follow-up of 0.9 ± 0.8 mm(2) . Volumetric changes were similar, and the distribution of neointimal hyperplasia peaked 1-2 mm distal to the carina. Change of lumen volume inversely correlated to the neointimal volume (R = -0.48, P0.001), but correlated positively to the change in stent volume (R = 0.52, P0.0001). By OCT, most CS struts were covered (100% [98.9, 100]) at the bifurcation site, whereas 61% of floating DES struts that crossed the sidebranch were covered by smooth tissue with a similar texture compared with neointima.Although neointimal hyperplasia accumulates within the CS stent mainly 1-2 mm distal to the carina, the self-expanding CS stent may be effective in maintaining an adequate patency in the sidebranch by continued stent expansion noted at follow-up.

We compared the mechanisms of lumen gain after Cappella Sideguard (CS) side branch (SB) bifurcation stent deployment versus a balloon-expandable stent in the corresponding main vessel (MV).The novel CS SB bifurcation stent is a self-expanding, thin-strut, nitinol device with anatomic flaring at the SB ostium.In 28 bifurcation lesions, intravascular ultrasound imaging of both the SB and the MV was performed both pre- and postintervention; vessel and lumen areas were measured every 1 mm over a 5 mm segment beginning at the carina.Although minimum lumen area (MLA) within the distal 5 mm segment beginning at the carina increased from 2.8 ± 1.3 mm(2) to 3.8 ± 1.1 mm(2), P0.001, in the SB and from 3.4 ± 1.4 mm(2) to 6.0 ± 1.1 mm(2), P0.001, in the MV, stent expansion (minimum stent area/distal reference lumen area) was significantly less in the SB compared with the MV (77.8 ± 21.3% vs. 91.6 ± 18.4%, P = 0.02). Post stenting, the MLA site was located at the carina more frequently in the SB (85.7%) than in the MV (60.7%), P = 0.04. Plaque volume in the 5 mm proximal to carina in the MV tended to decrease, whereas plaque volume in the SB increased slightly with no change in overall plaque volume in the 5-mm-long segment distal to the carina in the MV, suggesting plaque shift from the proximal MV to the SB.Acute CS lumen gain is less than the lumen gain of a balloon-expandable stent in the MV because of less aggressive acute expansion and/or the plaque shift from the proximal MV to the SB.

The limitation of exiting instruction-words software birthmark was high complexity, this paper introduced the idea of characteristics selection in text classification into the field of software birthmark, and proposed an instruction-words software birthmark selection method based on CHI ( statistics). The birthmark selection algorithm build sample program collections for protected program and extracted instruction-words from sample programs according to the instruction-words library firstly. After that, it calculated the statistics for each instructions-word in order to measure the correlation between instruction-words and program. Experiments showed that the birthmark selection algorithm could effectively bring down the scale of data, and significantly improved the credibility and robustness of the birthmark.