Deciphering recursive polyploidization in Lamiales and reconstructing their chromosome evolutionary trajectories.

Lamiales is an order of core eudicots with abundant diversity, and many Lamiales plants have important medicinal and ornamental values. Here, we comparatively reanalyzed 11 Lamiales species with well-assembled genome sequences and found evidence that Lamiales plants, in addition to a hexaploidization or whole-genome triplication (WGT) shared by core eudicots, experienced further polyploidization events, establishing new groups in the order. Notably, we identified a whole-genome duplication (WGD) occurred just before the split of Scrophulariaceae from the other Lamiales families, such as Acanthaceae, Bignoniaceae, and Lamiaceae, suggesting its likely being the causal reason for the establishment and fast divergence of these families. We also found that a WGT occurred ∼68 to 78 million years ago (Mya), near the split of Oleaceae from the other Lamiales families, implying that it may have caused their fast divergence and the establishment of the Oleaceae family. Then, by exploring and distinguishing intra- and intergenomic chromosomal homology due to recursive polyploidization and speciation, respectively, we inferred that the Lamiales ancestral cell karyotype had 11 proto-chromosomes. We reconstructed the evolutionary trajectories from these proto-chromosomes to form the extant chromosomes in each Lamiales plant under study. We must note that most of the inferred 11 proto-chromosomes, duplicated during a WGD thereafter, have been well preserved in jacaranda (Jacaranda mimosifolia) genome, showing the credibility of the present inference implementing a telomere-centric chromosome repatterning model. These efforts are important to understand genome repatterning after recursive polyploidization, especially shedding light on the origin of new plant groups and angiosperm cell karyotype evolution.

m6A-TCPred: a web server to predict tissue-conserved human m6A sites using machine learning approach.

BACKGROUND: N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification in eukaryotic cells that plays a crucial role in regulating various biological processes, and dysregulation of m6A status is involved in multiple human diseases including cancer contexts. A number of prediction frameworks have been proposed for high-accuracy identification of putative m6A sites, however, none have targeted for direct prediction of tissue-conserved m6A modified residues from non-conserved ones at base-resolution level. RESULTS: We report here m6A-TCPred, a computational tool for predicting tissue-conserved m6A residues using m6A profiling data from 23 human tissues. By taking advantage of the traditional sequence-based characteristics and additional genome-derived information, m6A-TCPred successfully captured distinct patterns between potentially tissue-conserved m6A modifications and non-conserved ones, with an average AUROC of 0.871 and 0.879 tested on cross-validation and independent datasets, respectively. CONCLUSION: Our results have been integrated into an online platform: a database holding 268,115 high confidence m6A sites with their conserved information across 23 human tissues; and a web server to predict the conserved status of user-provided m6A collections. The web interface of m6A-TCPred is freely accessible at: www.rnamd.org/m6ATCPred .

Platelet-Rich Plasma Injections for Shoulder Adhesive Capsulitis Are at Least Equivalent to Corticosteroid or Saline Solution Injections: A Systematic Review of Prospective Cohort Studies.

PURPOSE: To evaluate the role of platelet-rich plasma (PRP) for adhesive capsulitis (AC) as compared with other injectables. METHODS: A literature search of the PubMed and Embase online databases was performed to identify articles evaluating injection therapy for the treatment of AC. The inclusion criteria included prospective studies comparing PRP against alternative injectables with a minimum of 15 patients in each treatment arm and a minimum 12-week follow-up period. Pain scores, range of motion, and function scores were the primary outcomes assessed. RESULTS: Five articles comparing PRP with corticosteroid or saline solution injections met the inclusion criteria. A total of 157 patients were treated with PRP, with a follow-up duration ranging from 3 to 6 months. All 5 studies showed statistically significant improvements in pain scores, motion, and function scores in patients receiving PRP, corticosteroid, and saline solution injections. However, PRP was consistently superior on intergroup analyses in all but 1 study. In 4 studies, pain and function scores favored PRP over control at final follow-up (range in mean difference, -2.2 to 0.69 for visual analog scale pain score [n = 5] and -50.5 to -4.0 for Shoulder Pain and Disability Index score [n = 3]), whereas 3 studies found greater improvement in shoulder motion after PRP (range in mean difference, 0.7° to 34.3° for forward flexion and -2.3° to 20.4° for external rotation [n = 4]). One study found no significant difference between PRP and corticosteroid injections but noted that the results were comparable. CONCLUSIONS: According to a limited number of prospective studies, PRP injections for AC are at least equivalent to corticosteroid or saline solution injections and often lead to improved pain, motion, and functional outcomes at 3- to 6-month follow-up. Given the small number of studies, with design heterogeneity, there is insufficient evidence to routinely recommend PRP for AC. However, the results are promising and do support considering PRP as an adjunct treatment option for AC, especially for patients refractory and/or averse to corticosteroids or alternative treatment modalities. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.

RNADSN: Transfer-Learning 5-Methyluridine (m5U) Modification on mRNAs from Common Features of tRNA.

One of the most abundant non-canonical bases widely occurring on various RNA molecules is 5-methyluridine (m5U). Recent studies have revealed its influences on the development of breast cancer, systemic lupus erythematosus, and the regulation of stress responses. The accurate identification of m5U sites is crucial for understanding their biological functions. We propose RNADSN, the first transfer learning deep neural network that learns common features between tRNA m5U and mRNA m5U to enhance the prediction of mRNA m5U. Without seeing the experimentally detected mRNA m5U sites, RNADSN has already outperformed the state-of-the-art method, m5UPred. Using mRNA m5U classification as an additional layer of supervision, our model achieved another distinct improvement and presented an average area under the receiver operating characteristic curve (AUC) of 0.9422 and an average precision (AP) of 0.7855. The robust performance of RNADSN was also verified by cross-technical and cross-cellular validation. The interpretation of RNADSN also revealed the sequence motif of common features. Therefore, RNADSN should be a useful tool for studying m5U modification.

m6A-TSHub: Unveiling the Context-specific m6A Methylation and m6A-affecting Mutations in 23 Human Tissues.

As the most pervasive epigenetic marker present on mRNA and lncRNA, N6-methyladenosine (m6A) RNA methylation has been shown to participate in essential biological processes. Recent studies have revealed the distinct patterns of m6A methylome across human tissues, and a major challenge remains in elucidating the tissue-specific presence and circuitry of m6A methylation. We present here a comprehensive online platform m6A-TSHub for unveiling the context-specific m6A methylation and genetic mutations that potentially regulate m6A epigenetic mark. m6A-TSHub consists of four core components, including: (1) m6A-TSDB, a comprehensive database of 184,554 functionally annotated m6A sites derived from 23 human tissues and 499,369 m6A sites from 25 tumor conditions, respectively; (2) m6A-TSFinder, a web server for high-accuracy prediction of m6A methylation sites within a specific tissue from RNA sequences, which was constructed using multi-instance deep neural networks with gated attention; (3) m6A-TSVar, a web server for assessing the impact of genetic variants on tissue-specific m6A RNA modifications; and (4) m6A-CAVar, a database of 587,983 The Cancer Genome Atlas (TCGA) cancer mutations (derived from 27 cancer types) that were predicted to affect m6A modifications in the primary tissue of cancers. The database should make a useful resource for studying the m6A methylome and the genetic factors of epitranscriptome disturbance in a specific tissue (or cancer type). m6A-TSHub is accessible at www.xjtlu.edu.cn/biologicalsciences/m6ats.

m6A-Maize: Weakly supervised prediction of m6A-carrying transcripts and m6A-affecting mutations in maize (Zea mays).

With the rapid development of high-throughput sequencing techniques nowadays, extensive attention has been paid to epitranscriptomics, which covers more than 150 distinct chemical modifications to date. Among that, N6-methyladenosine (m6A) modification has the most abundant existence, and it is also significantly related to varieties of biological processes. Meanwhile, maize is the most important food crop and cultivated throughout the world. Therefore, the study of m6A modification in maize has both economic and academic value. In this research, we proposed a weakly supervised learning model to predict the situation of m6A modification in maize. The proposed model learns from low-resolution epitranscriptome datasets (e.g., MeRIP-seq), which predicts the m6A methylation status of given fragments or regions. By taking advantage of our prediction model, we further identified traits-associated SNPs that may affect (add or remove) m6A modifications in maize, which may provide potential regulatory mechanisms at epitranscriptome layer. Additionally, a centralized online-platform was developed for m6A study in maize, which contains 58,838 experimentally validated maize m6A-containing regions including training and testing datasets, and a database for 2,578 predicted traits-associated m6A-affecting maize mutations. Furthermore, the online web server based on proposed weakly supervised model is available for predicting putative m6A sites from user-uploaded maize sequences, as well as accessing the epitranscriptome impact of user-interested maize SNPs on m6A modification. In all, our work provided a useful resource for the study of m6A RNA methylation in maize species. It is freely accessible at www.xjtlu.edu.cn/biologicalsciences/maize.

m6AmPred: Identifying RNA N6, 2'-O-dimethyladenosine (m6Am) sites based on sequence-derived information.

N6,2'-O-dimethyladenosine (m6Am) is a reversible modification widely occurred on varied RNA molecules. The biological function of m6Am is yet to be known though recent studies have revealed its influences in cellular mRNA fate. Precise identification of m6Am sites on RNA is vital for the understanding of its biological functions. We present here m6AmPred, the first web server for in silico identification of m6Am sites from the primary sequences of RNA. Built upon the eXtreme Gradient Boosting with Dart algorithm (XgbDart) and EIIP-PseEIIP encoding scheme, m6AmPred achieved promising prediction performance with the AUCs greater than 0.954 when tested by 10-fold cross-validation and independent testing datasets. To critically test and validate the performance of m6AmPred, the experimentally verified m6Am sites from two data sources were cross-validated. The m6AmPred web server is freely accessible at: https://www.xjtlu.edu.cn/biologicalsciences/m6am, and it should make a useful tool for the researchers who are interested in N6,2'-O-dimethyladenosine RNA modification.

Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics.

Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects.

m7GDisAI: N7-methylguanosine (m7G) sites and diseases associations inference based on heterogeneous network.

BACKGROUND: Recent studies have confirmed that N7-methylguanosine (m7G) modification plays an important role in regulating various biological processes and has associations with multiple diseases. Wet-lab experiments are cost and time ineffective for the identification of disease-associated m7G sites. To date, tens of thousands of m7G sites have been identified by high-throughput sequencing approaches and the information is publicly available in bioinformatics databases, which can be leveraged to predict potential disease-associated m7G sites using a computational perspective. Thus, computational methods for m7G-disease association prediction are urgently needed, but none are currently available at present. RESULTS: To fill this gap, we collected association information between m7G sites and diseases, genomic information of m7G sites, and phenotypic information of diseases from different databases to build an m7G-disease association dataset. To infer potential disease-associated m7G sites, we then proposed a heterogeneous network-based model, m7G Sites and Diseases Associations Inference (m7GDisAI) model. m7GDisAI predicts the potential disease-associated m7G sites by applying a matrix decomposition method on heterogeneous networks which integrate comprehensive similarity information of m7G sites and diseases. To evaluate the prediction performance, 10 runs of tenfold cross validation were first conducted, and m7GDisAI got the highest AUC of 0.740(± 0.0024). Then global and local leave-one-out cross validation (LOOCV) experiments were implemented to evaluate the model's accuracy in global and local situations respectively. AUC of 0.769 was achieved in global LOOCV, while 0.635 in local LOOCV. A case study was finally conducted to identify the most promising ovarian cancer-related m7G sites for further functional analysis. Gene Ontology (GO) enrichment analysis was performed to explore the complex associations between host gene of m7G sites and GO terms. The results showed that m7GDisAI identified disease-associated m7G sites and their host genes are consistently related to the pathogenesis of ovarian cancer, which may provide some clues for pathogenesis of diseases. CONCLUSION: The m7GDisAI web server can be accessed at http://180.208.58.66/m7GDisAI/ , which provides a user-friendly interface to query disease associated m7G. The list of top 20 m7G sites predicted to be associted with 177 diseases can be achieved. Furthermore, detailed information about specific m7G sites and diseases are also shown.

m6A-Atlas: a comprehensive knowledgebase for unraveling the N6-methyladenosine (m6A) epitranscriptome.

N 6-Methyladenosine (m6A) is the most prevalent RNA modification on mRNAs and lncRNAs. It plays a pivotal role during various biological processes and disease pathogenesis. We present here a comprehensive knowledgebase, m6A-Atlas, for unraveling the m6A epitranscriptome. Compared to existing databases, m6A-Atlas features a high-confidence collection of 442 162 reliable m6A sites identified from seven base-resolution technologies and the quantitative (rather than binary) epitranscriptome profiles estimated from 1363 high-throughput sequencing samples. It also offers novel features, such as; the conservation of m6A sites among seven vertebrate species (including human, mouse and chimp), the m6A epitranscriptomes of 10 virus species (including HIV, KSHV and DENV), the putative biological functions of individual m6A sites predicted from epitranscriptome data, and the potential pathogenesis of m6A sites inferred from disease-associated genetic mutations that can directly destroy m6A directing sequence motifs. A user-friendly graphical user interface was constructed to support the query, visualization and sharing of the m6A epitranscriptomes annotated with sites specifying their interaction with post-transcriptional machinery (RBP-binding, microRNA interaction and splicing sites) and interactively display the landscape of multiple RNA modifications. These resources provide fresh opportunities for unraveling the m6A epitranscriptomes. m6A-Atlas is freely accessible at: www.xjtlu.edu.cn/biologicalsciences/atlas.

RMDisease: a database of genetic variants that affect RNA modifications, with implications for epitranscriptome pathogenesis.

Deciphering the biological impacts of millions of single nucleotide variants remains a major challenge. Recent studies suggest that RNA modifications play versatile roles in essential biological mechanisms, and are closely related to the progression of various diseases including multiple cancers. To comprehensively unveil the association between disease-associated variants and their epitranscriptome disturbance, we built RMDisease, a database of genetic variants that can affect RNA modifications. By integrating the prediction results of 18 different RNA modification prediction tools and also 303,426 experimentally-validated RNA modification sites, RMDisease identified a total of 202,307 human SNPs that may affect (add or remove) sites of eight types of RNA modifications (m6A, m5C, m1A, m5U, Ψ, m6Am, m7G and Nm). These include 4,289 disease-associated variants that may imply disease pathogenesis functioning at the epitranscriptome layer. These SNPs were further annotated with essential information such as post-transcriptional regulations (sites for miRNA binding, interaction with RNA-binding proteins and alternative splicing) revealing putative regulatory circuits. A convenient graphical user interface was constructed to support the query, exploration and download of the relevant information. RMDisease should make a useful resource for studying the epitranscriptome impact of genetic variants via multiple RNA modifications with emphasis on their potential disease relevance. RMDisease is freely accessible at: www.xjtlu.edu.cn/biologicalsciences/rmd.

m5UPred: A Web Server for the Prediction of RNA 5-Methyluridine Sites from Sequences.

As one of the widely occurring RNA modifications, 5-methyluridine (m5U) has recently been shown to play critical roles in various biological functions and disease pathogenesis, such as under stress response and during breast cancer development. Precise identification of m5U sites on RNA is vital for the understanding of the regulatory mechanisms of RNA life. We present here m5UPred, the first web server for in silico identification of m5U sites from the primary sequences of RNA. Built upon the support vector machine (SVM) algorithm and the biochemical encoding scheme, m5UPred achieved reasonable prediction performance with the area under the receiver operating characteristic curve (AUC) greater than 0.954 by 5-fold cross-validation and independent testing datasets. To critically test and validate the performance of our newly proposed predictor, the experimentally validated m5U sites were further separated by high-throughput sequencing techniques (miCLIP-Seq and FICC-Seq) and cell types (HEK293 and HAP1). When tested on cross-technique and cross-cell-type validation using independent datasets, m5UPred achieved an average AUC of 0.922 and 0.926 under mature mRNA mode, respectively, showing reasonable accuracy and reliability. The m5UPred web server is freely accessible now and it should make a useful tool for the researchers who are interested in m5U RNA modification.

DRUM: Inference of Disease-Associated m6A RNA Methylation Sites From a Multi-Layer Heterogeneous Network.

Recent studies have revealed that the RNA N 6-methyladenosine (m6A) modification plays a critical role in a variety of biological processes and associated with multiple diseases including cancers. Till this day, transcriptome-wide m6A RNA methylation sites have been identified by high-throughput sequencing technique combined with computational methods, and the information is publicly available in a few bioinformatics databases; however, the association between individual m6A sites and various diseases are still largely unknown. There are yet computational approaches developed for investigating potential association between individual m6A sites and diseases, which represents a major challenge in the epitranscriptome analysis. Thus, to infer the disease-related m6A sites, we implemented a novel multi-layer heterogeneous network-based approach, which incorporates the associations among diseases, genes and m6A RNA methylation sites from gene expression, RNA methylation and disease similarities data with the Random Walk with Restart (RWR) algorithm. To evaluate the performance of the proposed approach, a ten-fold cross validation is performed, in which our approach achieved a reasonable good performance (overall AUC: 0.827, average AUC 0.867), higher than a hypergeometric test-based approach (overall AUC: 0.7333 and average AUC: 0.723) and a random predictor (overall AUC: 0.550 and average AUC: 0.486). Additionally, we show that a number of predicted cancer-associated m6A sites are supported by existing literatures, suggesting that the proposed approach can effectively uncover the underlying epitranscriptome circuits of disease mechanisms. An online database DRUM, which stands for disease-associated ribonucleic acid methylation, was built to support the query of disease-associated RNA m6A methylation sites, and is freely available at: www.xjtlu.edu.cn/biologicalsciences/drum.

Texture Feature Extraction and Analysis for Polyp Differentiation via Computed Tomography Colonography.

Image textures in computed tomography colonography (CTC) have great potential for differentiating non-neoplastic from neoplastic polyps and thus can advance the current CTC detection-only paradigm to a new level with diagnostic capability. However, image textures are frequently compromised, particularly in low-dose CT imaging. Furthermore, texture feature extraction may vary, depending on the polyp spatial orientation variation, resulting in variable results. To address these issues, this study proposes an adaptive approach to extract and analyze the texture features for polyp differentiation. Firstly, derivative (e.g. gradient and curvature) operations are performed on the CT intensity image to amplify the textures with adequate noise control. Then Haralick co-occurrence matrix (CM) is used to calculate texture measures along each of the 13 directions (defined by the first and second order image voxel neighbors) through the polyp volume in the intensity, gradient and curvature images. Instead of taking the mean and range of each CM measure over the 13 directions as the so-called Haralick texture features, Karhunen-Loeve transform is performed to map the 13 directions into an orthogonal coordinate system so that the resulted texture features are less dependent on the polyp orientation variation. These simple ideas for amplifying textures and stabilizing spatial variation demonstrated a significant impact for the differentiating task by experiments using 384 polyp datasets, of which 52 are non-neoplastic polyps and the rest are neoplastic polyps. By the merit of area under the curve of receiver operating characteristic, the innovative ideas achieved differentiation capability of 0.8016, indicating the CTC diagnostic feasibility.

An adaptive paradigm for computer-aided detection of colonic polyps.

Most previous efforts in developing computer-aided detection (CADe) of colonic polyps apply similar measures or parameters to detect polyps regardless of their locations under an implicit assumption that all the polyps reside in a similar local environment, e.g. on a relatively flat colon wall. In reality, this implicit assumption is frequently invalid, because the haustral folds can have a very different local environment from that of the relatively flat colon wall. We conjecture that this assumption may be a major cause of missing the detection of polyps, especially small polyps (<10 mm linear size) located on the haustral folds. In this paper, we take the concept of adaptiveness and present an adaptive paradigm for CADe of colonic polyps. Firstly, we decompose the complicated colon structure into two simplified sub-structures, each of which has similar properties, of (1) relatively flat colon wall and (2) ridge-shaped haustral folds. Then we develop local environment descriptions to adaptively reflect each of these two simplified sub-structures. To show the impact of the adaptiveness of the local environment descriptions upon the polyp detection task, we focus on the local geometrical measures of the volume data for both the detection of initial polyp candidates (IPCs) and the reduction of false positives (FPs) in the IPC pool. The experimental outcome using the local geometrical measures is very impressive such that not only the previously-missed small polyps on the folds are detected, but also the previously miss-removed small polyps on the folds during FP reduction are retained. It is expected that this adaptive paradigm will have a great impact on detecting the small polyps, measuring their volumes and volume changes over time, and optimizing their management plan.

Texture feature analysis for computer-aided diagnosis on pulmonary nodules.

Differentiation of malignant and benign pulmonary nodules is of paramount clinical importance. Texture features of pulmonary nodules in CT images reflect a powerful character of the malignancy in addition to the geometry-related measures. This study first compared three well-known types of two-dimensional (2D) texture features (Haralick, Gabor, and local binary patterns or local binary pattern features) on CADx of lung nodules using the largest public database founded by Lung Image Database Consortium and Image Database Resource Initiative and then investigated extension from 2D to three-dimensional (3D) space. Quantitative comparison measures were made by the well-established support vector machine (SVM) classifier, the area under the receiver operating characteristic curves (AUC) and the p values from hypothesis t tests. While the three feature types showed about 90% differentiation rate, the Haralick features achieved the highest AUC value of 92.70% at an adequate image slice thickness, where a thinner or thicker thickness will deteriorate the performance due to excessive image noise or loss of axial details. Gain was observed when calculating 2D features on all image slices as compared to the single largest slice. The 3D extension revealed potential gain when an optimal number of directions can be found. All the observations from this systematic investigation study on the three feature types can lead to the conclusions that the Haralick feature type is a better choice, the use of the full 3D data is beneficial, and an adequate tradeoff between image thickness and noise is desired for an optimal CADx performance. These conclusions provide a guideline for further research on lung nodule differentiation using CT imaging.

Fast and adaptive detection of pulmonary nodules in thoracic CT images using a hierarchical vector quantization scheme.

Computer-aided detection (CADe) of pulmonary nodules is critical to assisting radiologists in early identification of lung cancer from computed tomography (CT) scans. This paper proposes a novel CADe system based on a hierarchical vector quantization (VQ) scheme. Compared with the commonly-used simple thresholding approach, the high-level VQ yields a more accurate segmentation of the lungs from the chest volume. In identifying initial nodule candidates (INCs) within the lungs, the low-level VQ proves to be effective for INCs detection and segmentation, as well as computationally efficient compared to existing approaches. False-positive (FP) reduction is conducted via rule-based filtering operations in combination with a feature-based support vector machine classifier. The proposed system was validated on 205 patient cases from the publically available online Lung Image Database Consortium database, with each case having at least one juxta-pleural nodule annotation. Experimental results demonstrated that our CADe system obtained an overall sensitivity of 82.7% at a specificity of 4 FPs/scan. Especially for the performance on juxta-pleural nodules, we observed 89.2% sensitivity at 4.14 FPs/scan. With respect to comparable CADe systems, the proposed system shows outperformance and demonstrates its potential for fast and adaptive detection of pulmonary nodules via CT imaging.

Volumetric texture features from higher-order images for diagnosis of colon lesions via CT colonography.

PURPOSE: Differentiation of colon lesions according to underlying pathology, e.g., neoplastic and non-neoplastic lesions, is of fundamental importance for patient management. Image intensity-based textural features have been recognized as useful biomarker for the differentiation task. In this paper, we introduce texture features from higher-order images, i.e., gradient and curvature images, beyond the intensity image, for that task. METHODS: Based on the Haralick texture analysis method, we introduce a virtual pathological model to explore the utility of texture features from high-order differentiations, i.e., gradient and curvature, of the image intensity distribution. The texture features were validated on a database consisting of 148 colon lesions, of which 35 are non-neoplastic lesions, using the support vector machine classifier and the merit of area under the curve (AUC) of the receiver operating characteristics. RESULTS: The AUC of classification was improved from 0.74 (using the image intensity alone) to 0.85 (by also considering the gradient and curvature images) in differentiating the neoplastic lesions from non-neoplastic ones, e.g., hyperplastic polyps from tubular adenomas, tubulovillous adenomas and adenocarcinomas. CONCLUSIONS: The experimental results demonstrated that texture features from higher-order images can significantly improve the classification accuracy in pathological differentiation of colorectal lesions. The gain in differentiation capability shall increase the potential of computed tomography colonography for colorectal cancer screening by not only detecting polyps but also classifying them for optimal polyp management for the best outcome in personalized medicine.

Integration of 3D scale-based pseudo-enhancement correction and partial volume image segmentation for improving electronic colon cleansing in CT colonograpy.

Orally administered tagging agents are usually used in CT colonography (CTC) to differentiate residual bowel content from native colonic structures. However, the high-density contrast agents tend to introduce pseudo-enhancement (PE) effect on neighboring soft tissues and elevate their observed CT attenuation value toward that of the tagged materials (TMs), which may result in an excessive electronic colon cleansing (ECC) since the pseudo-enhanced soft tissues are incorrectly identified as TMs. To address this issue, we integrated a 3D scale-based PE correction into our previous ECC pipeline based on the maximum a posteriori expectation-maximization partial volume (PV) segmentation. The newly proposed ECC scheme takes into account both the PE and PV effects that commonly appear in CTC images. We evaluated the new scheme on 40 patient CTC scans, both qualitatively through display of segmentation results, and quantitatively through radiologists' blind scoring (human observer) and computer-aided detection (CAD) of colon polyps (computer observer). Performance of the presented algorithm has shown consistent improvements over our previous ECC pipeline, especially for the detection of small polyps submerged in the contrast agents. The CAD results of polyp detection showed that 4 more submerged polyps were detected for our new ECC scheme over the previous one.

Endomorphin analogues with mixed µ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking ß-arrestin2 recruitment activity.

Analogues of endomorphin (Dmt-Pro-Xaa-Xaa-NH2) modified at position 4 or at positions 4 and 3, and tripeptides (Dmt-Pro-Xaa-NH2) modified at position 3, with various phenylalanine analogues (Xaa=Trp, 1-Nal, 2-Nal, Tmp, Dmp, Dmt) were synthesized and their effects on in vitro opioid activity were investigated. Most of the peptides exhibited high µ-opioid (MOP) receptor binding affinity (KiMOP=0.13-0.81nM), modest MOP-selectivity (Kiδ-opioid (DOP)/KiMOP=3.5-316), and potent functional MOP agonism (GPI, IC50=0.274-249nM) without DOP and κ-opioid (KOP) receptor agonism. Among them, compounds 7 (Dmt-Pro-Tmp-Tmp-NH2) and 9 (Dmt-Pro-1-Nal-NH2) were opioids with potent mixed MOP receptor agonism/DOP receptor antagonism and devoid of ß-arrestin2 recruitment activity. They may offer a unique template for the discovery of potent analgesics that produce less respiratory depression, less gastrointestinal dysfunction and that have a lower propensity to induce tolerance and dependence compared with morphine.